The Topic of the Lesson “Osteomyelitis.”

The topic of the lesson “Osteomyelitis.”

According to the evidence-based data from UpToDate extracted March of 19, 2020 Provide a conspectus in a format of .ppt (.pptx) presentation of not less than 50 slides containing information on:

1. Classification 2. Etiology 3. Pathogenesis 4. Diagnostic 5. Differential diagnostic 6. Treatment With 10 (ten) multiple answer questions.

Pathogenesis of osteomyelitis - UpToDate

Official reprint from UpToDate® www.uptodate.com ©2020 UpToDate, Inc. and/or its affiliates. All Rights Reserved. Print Options Print | Back Text References Graphics Pathogenesis of osteomyelitis Contributor Disclosures Author: Madhuri M Sopirala, MD, MPH Section Editor: Denis Spelman, MBBS, FRACP, FRCPA, MPH Deputy Editor: Elinor L Baron, MD, DTMH

All topics are updated as new evidence becomes available and our peer review process is complete.

Literature review current through: Feb 2020. | This topic last updated: Jan 17, 2020.

INTRODUCTION

Osteomyelitis is an infection involving bone.

The pathogenesis and pathology of osteomyelitis will be reviewed here. The clinical manifestations, diagnosis, and treatment of osteomyelitis are discussed separately. (See "Osteomyelitis in adults: Clinical manifestations and diagnosis" and "Approach to imaging modalities in the setting of suspected nonvertebral osteomyelitis" and "Osteomyelitis associated with open fractures in adults" and "Clinical manifestations, diagnosis, and management of diabetic infections of the lower extremities" and "Vertebral osteomyelitis and discitis in adults".)

CLASSIFICATION

Osteomyelitis may be divided into two major categories based upon the pathogenesis of infection: (1) hematogenous osteomyelitis and (2) nonhematogenous osteomyelitis, which develops adjacent to a contiguous focus of infection or via direct inoculation of infection into the bone [1-3]. (See "Osteomyelitis in adults: Clinical manifestations and diagnosis", section on 'Classification'.)

Either hematogenous or contiguous-focus osteomyelitis can be classified as acute or chronic. Acute osteomyelitis evolves over several days to weeks and can progress to a chronic infection [1]. The hallmark of chronic osteomyelitis is the presence of dead bone (sequestrum). Other common features of chronic osteomyelitis include involucrum (reactive bony encasement of the sequestrum), local bone loss, and, if there is extension through cortical bone, sinus tracts.

Brodie abscess is a form of subacute osteomyelitis that is usually hematogenous in origin but can occur as a the result of trauma; the classic presentation of Brodie abscess consists of a cavity filled with suppurative and/or granulation in a long bone metaphysis, surrounded by dense fibrous tissue and sclerotic bone [4].

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PATHOGENESIS

Normal bone is highly resistant to infection. Osteomyelitis develops when there is a large inoculation of organisms, presence of bone damage, and/or presence of hardware or other foreign material.

The pathogenesis of osteomyelitis is multifactorial and poorly understood; important factors include the virulence of the infecting organism(s), the host immune status, and the bone vascularity.

Bacteria have a number of virulence determinants that may contribute to development of osteomyelitis in the appropriate clinical setting. Staphylococcus aureus, the most common cause of osteomyelitis, has been used extensively as a model to study pathogenesis and is therefore discussed in detail in this section. It is an important cause (though not the only cause) of hematogenous and contiguous focus osteomyelitis. S. aureus produces several extracellular and cell-associated factors that may contribute to virulence by promoting bacterial adherence, resistance to host defense mechanisms, and proteolytic activity.

Bacterial adherence — Adherence appears to play a central role in the early stages of S. aureus- induced osteomyelitis or arthritis. S. aureus adheres to a number of components of bone matrix including fibrinogen, fibronectin, laminin, collagen, bone sialoglycoprotein, and clumping factor A [5-9]. Adherence is mediated by expression of specific adhesins, called microbial surface components recognizing adhesive matrix molecules [5,10].

The potential importance of adhesins was illustrated in a study in which mice were inoculated with positive and negative mutants for the collagen adhesin gene: septic arthritis occurred with greater frequency in the mutant-positive compared with mutant-negative strains (>70 versus 27 percent) [11]. The adhesin-positive strains were also associated with the production of high levels of immunoglobulin G (IgG) and interleukin 6. In other experimental studies, S. aureus adhesion was blocked by antibodies directed against the collagen receptor [12]. It has been speculated that bone and other invasive S. aureus infections might be prevented by an adhesin-derived vaccine [13].

Collagen-binding adhesin (CNA) of S. aureus is a virulence factor for arthritis in several animal models [14,15]. The expression of CNA permits the attachment of pathogen to cartilage [16]. How CNA contributes to virulence and whether it is important in humans are unclear.

Fibronectin-binding protein rapidly coats implanted foreign bodies in vivo and adheres to biomaterials coated with host proteins. It may be particularly important in infections associated with prosthetic joints [7]. Atomic-force microscopy has demonstrated that fibronectin-binding proteins A and B (FnBPA and FnBPB) form bonds with host fibronectin and may play a key role in binding S. aureus to implants [17]. (See "Prosthetic joint infection: Epidemiology, microbiology, clinical manifestations, and diagnosis".)

Resistance to host defense — The ability of microorganisms to resist host defense mechanisms at the cellular and matrix levels presents difficulties in the management of osteomyelitis.

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As an example, S. aureus can survive intracellularly in cultured osteoblasts. Persistence of intracellular pathogens within osteoblasts may also be an important factor in the pathogenesis of osteomyelitis. When digested by osteoblasts, S. aureus undergoes phenotypic alteration, which renders it more resistant to the action of antimicrobials. This may explain in part the high relapse rate of osteomyelitis treated with antimicrobials for a short duration [2,18]. Osteoblast persistence of S. aureus in chronic osteomyelitis has been described [19,20].

Arachidonic acid metabolites, such as prostaglandin E2, a strong osteoclast agonist, decrease the bacterial inoculum needed to produce infection.

S. aureus expresses a 42-kDa protein, protein A, which is bound covalently to the outer peptidoglycan layer of their cell walls. Protein A binds to the Fc portion of IgG on polymorphonuclear leukocytes, interfering with opsonization and phagocytosis of S. aureus [21]. Loss of protein A activity reduces virulence [22].

S. aureus secretes two toxins, exotoxin and toxic shock syndrome toxin (TSST-) 1, which exert important effects on the immune system when administered parenterally. The toxins act as superantigens and suppress plasma cell differentiation; they also stimulate production of cytokines, such as interleukin 1 [23], interferon-gamma, and tumor necrosis factor-alpha [24]. Animals infected with strains of S. aureus isogenic for TSST-1 develop frequent and severe arthritis [25]. Staphylococcal enterotoxin and TSST-1 subvert the cellular and humoral immune system, which may determine whether a local infection is eliminated or develops into osteomyelitis or septic arthritis.

HISTOPATHOLOGY

Overview — Acute osteomyelitis demonstrates suppurative infection with acute inflammatory cells, accompanied by edema, vascular congestion, and small vessel thrombosis (picture 1 and picture 2). In early acute disease, the vascular supply to the bone is compromised by infection extending into the surrounding soft tissue. When both the medullary and periosteal blood supplies are compromised, large areas of dead bone (sequestra) may form [26]. Within this necrotic and ischemic tissue, bacteria can be difficult to eradicate even in the setting of an intense host response, surgery, and antibiotic therapy.

Clinically and histologically, acute osteomyelitis blends into chronic osteomyelitis. Pathologic features of chronic osteomyelitis include necrotic bone, the formation of new bone, and polymorphonuclear leukocyte exudation joined by large numbers of lymphocytes, histiocytes, and occasional plasma cells (picture 3).

Necrosis of normal tissue is an important feature of osteomyelitis. Dead bone is absorbed by the action of granulation tissue developing at its surface. Absorption takes place earliest and most rapidly at the junction of living and necrotic bone. If the area of the dead bone is small, it is entirely destroyed by granulation tissue, leaving a cavity behind. The necrotic cancellous (trabecular) bone in localized

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osteomyelitis, even though extensive, is usually absorbed. Some of the dead cortical bone is gradually detached from living bone to form a sequestrum [3,27].

Host defense and mesenchymal cells, mainly the polymorphonuclear leukocytes, macrophages, and the osteoclasts, elaborate proteolytic enzymes that break down organic elements in the dead bone (picture 2). Because of lost blood supply, dead bone appears whiter than living bone. Cancellous bone is absorbed rapidly and may be completely sequestrated or destroyed in two to three weeks, but necrotic cortex may require two weeks to six months for separation. After complete separation, the dead bone is slowly eroded by granulation tissue and absorbed.

New bone formation is another characteristic feature of osteomyelitis. New bone forms from the surviving fragments of periosteum, endosteum, and the cortex in the region of the infection and is produced by a vascular reaction to the infection. New bone may be formed along the intact periosteal and endosteal surfaces and may also arise when the periosteum forms an encasing sheath of live bone (involucrum) surrounding the dead bone. Involucrum is irregular and is often perforated by openings through which pus may track into the surrounding soft tissues and eventually to the skin surfaces through a sinus tract. The involucrum can gradually increase in density and thickness to form part or all of a new shaft.

New bone increases in amount and density for weeks or months, according to the size of the bone and the extent and duration of infection. Endosteal new bone may proliferate and obstruct the medullary canal. After host defense removal or surgical removal of the sequestrum, the body, especially in children, may fill the remaining cavity with new bone. However, in adults, the cavity may persist or the space may be filled with fibrous tissue that may connect with the skin surface via a sinus tract.

The surviving bone in the osteomyelitis field usually becomes osteoporotic during the active period of infection. Osteoporosis is the result of the inflammatory reaction and atrophy disuse. After the infection subsides, bone density increases partially from reuse (eg, of a limb); the bone may undergo extensive transformation to conform to areas of new mechanical stresses. It may be difficult to distinguish between the old living bone and the newly formed bone as time passes. All traces of osteomyelitis can disappear in children and, to a lesser extent, in adults.

Differences by age — There are basic differences in the pathology of osteomyelitis in infants, children, and adults.

In neonates, small capillaries cross the epiphyseal growth plate and permit extension of infection into the epiphysis and joint space. The cortical bone of the neonate and infant is thin and loose, consisting predominantly of woven bone, which permits escape of the pressure caused by infection, but promotes rapid spread of the infection directly into the subperiosteal region. A large sequestrum is not produced because extensive infarction of the cortex does not occur; however, a large subperiosteal abscess can form [28,29].

In children older than one year, infection presumably starts in the metaphyseal sinusoidal veins and is contained by the growth plate. Dye injection experiments described in the 1920s have depicted

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metaphyseal vessels as a series of capillary loops terminating adjacent to the growth plate and expanding into dilated venous sinusoids resulting in sluggish blood flow, thus predisposing to bacterial deposition [30]. Subsequently, electron micrographic studies have described rapidly growing vessels with a single layer of discontinuous endothelium at their tips, through which bacteria may pass during an episode of bacteremia, thus initiating osteomyelitis [31,32]. An experimental avian model confirmed that bacteria are deposited initially at the end of metaphyseal tunnels that provide a framework for the rapidly growing metaphyseal vessels. The presence of endothelial gaps in the tips of metaphyseal vessels, regardless of blood flow rates, may play a critical role in the initiation of osteomyelitis [33]. The joint is spared unless the metaphysis is intracapsular. The infection spreads laterally where it breaks through the cortex and lifts the loose periosteum to form a subperiosteal abscess [29,34].

In adults, the growth plate has resorbed, and the infection may again extend to the joint spaces as in infants. In addition, the periosteum is firmly attached to the underlying bone; as a result, subperiosteal abscess formation and intense periosteal proliferation are less frequently seen. The infection can erode through the periosteum, forming a draining sinus tract(s) [35].

CLINICAL FORMS

Issues related to clinical manifestations and diagnosis of osteomyelitis are discussed separately. (See "Osteomyelitis in adults: Clinical manifestations and diagnosis".)

Hematogenous osteomyelitis — Hematogenous osteomyelitis is the most common form of osteomyelitis in infants and children [1]. The pathogenesis is discussed separately. (See "Hematogenous osteomyelitis in children: Epidemiology, pathogenesis, and microbiology".)

In adults, vertebral osteomyelitis is the most common form of hematogenous osteomyelitis; the pathogenesis is discussed separately. (See "Vertebral osteomyelitis and discitis in adults", section on 'Pathogenesis'.)

Other sites of hematogenous osteomyelitis in adults include the long bones, pelvis, and clavicle. (See "Osteomyelitis in adults: Clinical manifestations and diagnosis", section on 'Hematogenous osteomyelitis'.)

In people who inject drugs (PWID), osteomyelitis assumes an axial distribution involving vertebral column, especially the lumbar spine; the reason for the axial distribution in this patient population is uncertain. Osteomyelitis can also occur in the sternum, extremities and sacroiliac joints. Common microbiologic causes include S. aureus, Pseudomonas spp, and Candida spp. In addition, osteomyelitis due to oral flora can occur osteomyelitis among PWID who lick the needle tip or skin before infection [36].

Tuberculous osteomyelitis usually occurs from reactivation of tuberculous bacilli lodged in bone during the mycobacteremia occurring at the time of the primary infection. (See "Skeletal tuberculosis", section on 'Spondylitis (Pott disease)'.)

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Nonhematogenous osteomyelitis — Nonhematogenous osteomyelitis, which develops adjacent to a contiguous focus of infection or via direct inoculation of infection into the bone (via trauma, surgery or hardware placement). The clinical manifestations and diagnosis of nonhematogenous osteomyelitis are discussed separately. (See "Osteomyelitis in adults: Clinical manifestations and diagnosis", section on 'Nonhematogenous osteomyelitis'.)

Skull base osteomyelitis can occur as a complication of otogenic, sinogenic, odontogenic, or rhinogenic infections [37]. The pathogenesis is not fully understood; it may include a combination of factors including hypoperfusion and diminished immune response. In addition, use of water irrigation for cerumen disimpaction may reduce the cerumen lysozyme content, leading to alkaline pH and increased susceptibility to Pseudomonas infection [38]. Malignant otitis externa can spread from the external auditory canal to the skull base [39,40]. Potential complications include involvement cranial nerves, the parotid gland, the temporomandibular joint, the carotid artery, and the jugular vein.

Osteomyelitis involving the hand can occur as a result of animal or human bite. Pathogens include aerobic and anaerobic bacteria; streptococcal and staphylococcal species are most commonly reported [41-43]. (See "Animal bites (dogs, cats, and other animals): Evaluation and management" and "Human bites: Evaluation and management".)

Contiguous osteomyelitis associated with vascular insufficiency occurs most commonly in the setting of diabetes mellitus and/or peripheral vascular disease. Inadequate tissue perfusion and predisposes to development of osteomyelitis following minor foot trauma [35].

SUMMARY

● The hallmark of chronic osteomyelitis is the presence of dead bone (sequestrum). Other common features of chronic osteomyelitis include involucrum (reactive bony encasement of the sequestrum), local bone loss, and, if there is extension through cortical bone, sinus tracts. (See 'Introduction' above.)

● The pathogenesis of osteomyelitis is multifactorial and poorly understood. Some important factors include virulence of the infecting organism(s), underlying immune status of the host, and the type, location, and vascularity of the bone. (See 'Pathogenesis' above.)

● Staphylococcus aureus can survive intracellularly in cultured osteoblasts. Persistence of intracellular pathogens within osteoblasts may also be an important factor in the pathogenesis of osteomyelitis. When digested by osteoblasts, S. aureus undergoes phenotypic alteration, which renders it more resistant to the action of antimicrobials. This may explain in part the high relapse rate of osteomyelitis treated with antimicrobials for a short duration. (See 'Resistance to host defense' above.)

● Acute osteomyelitis demonstrates suppurative infection with acute inflammatory cells, accompanied

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by edema, vascular congestion, and small vessel thrombosis (picture 1 and picture 2). Pathologic features of chronic osteomyelitis include necrotic bone, the formation of new bone, and polymorphonuclear leukocyte exudation joined by large numbers of lymphocytes, histiocytes, and occasional plasma cells (picture 3). (See 'Histopathology' above.)

● New bone formation is another characteristic feature of osteomyelitis. New bone forms from the surviving fragments of periosteum, endosteum, and the cortex in the region of the infection and is produced by a vascular reaction to the infection. (See 'Histopathology' above.)

● The surviving bone in the osteomyelitis field usually becomes osteoporotic during the active period of infection. Osteoporosis is the result of the inflammatory reaction and atrophy disuse. (See 'Histopathology' above.)

ACKNOWLEDGMENT

The editors of UpToDate would like to acknowledge LiYan Yin, MD, and Jason Calhoun, MD, who contributed to earlier versions of this topic review.

Use of UpToDate is subject to the Subscription and License Agreement.

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17. Buck AW, Fowler VG Jr, Yongsunthon R, et al. Bonds between fibronectin and fibronectin-binding proteins on Staphylococcus aureus and Lactococcus lactis. Langmuir 2010; 26:10764.

18. Norden CW. Lessons learned from animal models of osteomyelitis. Rev Infect Dis 1988; 10:103.

19. Webb LX, Wagner W, Carroll D, et al. Osteomyelitis and intraosteoblastic Staphylococcus aureus. J Surg Orthop Adv 2007; 16:73.

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21. Greenberg DP, Bayer AS, Cheung AL, Ward JI. Protective efficacy of protein A-specific antibody against bacteremic infection due to Staphylococcus aureus in an infant rat model. Infect Immun 1989; 57:1113.

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23. Nair S, Song Y, Meghji S, et al. Surface-associated proteins from Staphylococcus aureus https://www.uptodate.com/...rint?search=osteomyelitis&source=search_result&selectedTitle=7~150&usage_type=default&display_rank=7[19.03.2020 15:32:22] Pathogenesis of osteomyelitis - UpToDate

demonstrate potent bone resorbing activity. J Bone Miner Res 1995; 10:726.

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37. Khan MA, Quadri SAQ, Kazmi AS, et al. A Comprehensive Review of Skull Base Osteomyelitis: Diagnostic and Therapeutic Challenges among Various Presentations. Asian J Neurosurg 2018; 13:959.

38. Driscoll PV, Ramachandrula A, Drezner DA, et al. Characteristics of cerumen in diabetic patients: a key to understanding malignant external otitis? Otolaryngol Head Neck Surg 1993; 109:676.

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39. Alva B, Prasad KC, Prasad SC, Pallavi S. Temporal bone osteomyelitis and temporoparietal abscess secondary to malignant otitis externa. J Laryngol Otol 2009; 123:1288.

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Topic 7660 Version 18.0

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GRAPHICS

Acute osteomyelitis

Light micrograph of acute osteomyelitis of the tibia shows many disconnected bony trabeculae in a sea of inflammatory cells (red arrow) and a single multinucleated giant cell (black arrow). The surfaces of the trabeculae (white arrows) have a few undifferentiated, spindle-shaped connective tissue elements. There is little evidence of active bone formation or bone resorption.

Courtesy of Jon Mader, MD.

Graphic 72714 Version 3.0

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Early repair in acute osteomyelitis

Light micrograph in acute osteomyelitis of the tibial articular apparatus. The presence of whorls of chondrocytes (arrows) indicates early tissue repair in which multinucleated osteoclasts (dashed arrows) are actively remodeling the subchondral region. Bone (arrowhead) has replaced the mature lamellar structure, and the medullary spaces are largely filled with inflammatory cells and fibrin.

Courtesy of Jon Mader, MD.

Graphic 62981 Version 3.0

Contributor Disclosures

Madhuri M Sopirala, MD, MPH Nothing to disclose Denis Spelman, MBBS, FRACP, FRCPA, MPH Nothing to disclose Elinor L Baron, MD, DTMH Nothing to disclose

Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are addressed by vetting through a multi-level review process, and through requirements for references to be provided to support the content. Appropriately referenced content is required of all authors and must conform to UpToDate standards of evidence.

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Chronic osteomyelitis

Light micrograph of chronic osteomyelitis of the tibia. Against a background of inflammatory cells (arrow), there are thickened bony trabeculae (arrowhead) lined by plump osteoblasts, which are actively forming bone. The accumulation of small dark cells (lymphocytes; dashed arrows) represent sites of perivascular inflammation.

Courtesy of Jon Mader, MD.

Graphic 53767 Version 4.0

Contributor Disclosures

Madhuri M Sopirala, MD, MPH Nothing to disclose Denis Spelman, MBBS, FRACP, FRCPA, MPH Nothing to disclose Elinor L Baron, MD, DTMH Nothing to disclose

Conflict of interest policy

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Contributor Disclosures

Madhuri M Sopirala, MD, MPH Nothing to disclose Denis Spelman, MBBS, FRACP, FRCPA, MPH Nothing to disclose Elinor L Baron, MD, DTMH Nothing to disclose

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https://www.uptodate.com/...rint?search=osteomyelitis&source=search_result&selectedTitle=7~150&usage_type=default&display_rank=7[19.03.2020 15:32:22] Approach to imaging modalities in the setting of suspected nonvertebral osteomyelitis - UpToDate

Official reprint from UpToDate® www.uptodate.com ©2020 UpToDate, Inc. and/or its affiliates. All Rights Reserved. Print Options Print | Back Text References Graphics Approach to imaging modalities in the setting of suspectedContributor Disclosures nonvertebral osteomyelitis

Author: Charles E Spritzer, MD Section Editor: Denis Spelman, MBBS, FRACP, FRCPA, MPH Deputy Editor: Elinor L Baron, MD, DTMH

All topics are updated as new evidence becomes available and our peer review process is complete.

Literature review current through: Feb 2020. | This topic last updated: Feb 28, 2020.

INTRODUCTION

Radiographic imaging is useful for confirming or excluding the diagnosis of osteomyelitis, delineating the extent of disease, and planning therapy (table 1). Imaging findings must be interpreted in clinical context [1]. Osteomyelitis may occur in any bone; the largest body of data on imaging modalities for evaluation of osteomyelitis comes from the literature on diabetic foot infections.

The benefits and limitations of plain radiographs, magnetic resonance imaging, computed tomography, nuclear modalities, and ultrasonography for the diagnosis of osteomyelitis will be reviewed here. An integrated diagnostic approach to evaluation of adults with suspected osteomyelitis is presented in detail separately. (See "Osteomyelitis in adults: Clinical manifestations and diagnosis", section on 'Clinical approach'.)

Issues related to radiographic imaging in the setting of suspected vertebral osteomyelitis and discitis are discussed separately. (See "Vertebral osteomyelitis and discitis in adults".)

PATHOPHYSIOLOGY OF OSTEOMYELITIS

Osteomyelitis can occur as a result of hematogenous seeding, contiguous spread of infection to bone from adjacent soft tissues and joints, or direct inoculation of infection into the bone as a result of trauma or surgery. The most commonly affected adults are individuals with poorly controlled diabetes, peripheral neuropathy, and vascular insufficiency who develop ulcers and subsequent osteomyelitis in one or more bones of the foot [2,3]. (See "Osteomyelitis in adults: Clinical manifestations and diagnosis", section on 'Classification'.)

In the setting of osteomyelitis, inflammatory exudate in the marrow causes elevated medullary pressure, which compresses vascular channels, leading to ischemia and bone necrosis. If the areas of necrotic https://www.uptodate.com/...rint?search=osteomyelitis&source=search_result&selectedTitle=3~150&usage_type=default&display_rank=3[19.03.2020 15:32:09] Approach to imaging modalities in the setting of suspected nonvertebral osteomyelitis - UpToDate

bone separate from the remaining viable bone, sequestra are formed. Surviving bone and periosteum ultimately produce a sheath of bone surrounding the area of necrosis, which is referred to as an involucrum. Both the sequestra and involucrum may be apparent radiographically (image 1 and image 2) [2,3].

Acute osteomyelitis refers to infection in the bone prior to development of sequestra, usually measured in days or weeks. In some forms of osteomyelitis, development of sequestra is relatively slow (such as vertebral osteomyelitis), while in others the development of sequestra occurs relatively rapidly (such as osteomyelitis in the setting of prosthetic devices or compound fractures) [1].

Following formation of sequestra, the infection is considered to be chronic osteomyelitis. Other hallmarks of chronic osteomyelitis include involucrum, local bone loss, and sinus tracts (extension of infection through cortical bone) (image 1 and image 2). Occasionally, pus may exist in an opening (cloaca) of involucrum.

SELECTING AN IMAGING MODALITY

The evaluation of suspected osteomyelitis includes radiographic imaging interpreted together with the clinical history, culture data, and laboratory results. The optimal imaging modality depends upon the specific clinical circumstances and should be tailored accordingly. An integrated diagnostic approach for osteomyelitis is outlined in detail separately. (See "Osteomyelitis in adults: Clinical manifestations and diagnosis", section on 'Clinical approach'.)

In general, if osteomyelitis is suspected based on clinical history and physical findings, imaging should begin with conventional radiographs (plain x-rays) of the involved area. A more sophisticated imaging modality should be pursued for patients with normal radiographs or radiographs suggestive of osteomyelitis without definitive characteristic features; such imaging may be used to establish a diagnosis of osteomyelitis and/or to define the extent of disease for surgical planning. In general, magnetic resonance imaging (MRI) is the imaging modality with greatest sensitivity for diagnosis of osteomyelitis; if MRI is contraindicated, a labeled leukocyte scan, sulfur colloid marrow scan, computed tomography (CT), or positron emission tomography/CT is appropriate [4-6]. MRI, CT, and ultrasonography may all be useful in assessing the associated soft tissue abnormalities.

IMAGING MODALITIES

The sensitivity of conventional radiographs for detection of acute osteomyelitis is limited, and the specificity of some imaging modalities may be limited by confounding bony pathology. Negative predictive values are high for magnetic resonance imaging (MRI) and radionuclide studies.

Conventional radiography — Conventional radiography (eg, plain x-ray) is a reasonable initial imaging modality for evaluation of suspected osteomyelitis in patients with at least two weeks of clinical https://www.uptodate.com/...rint?search=osteomyelitis&source=search_result&selectedTitle=3~150&usage_type=default&display_rank=3[19.03.2020 15:32:09] Approach to imaging modalities in the setting of suspected nonvertebral osteomyelitis - UpToDate

symptoms; it is not adequate for detection of early osteomyelitis [7]. Conventional radiographs are useful for identification of noninfectious pathology and for identifying air within soft tissues (image 3). The sensitivity of conventional radiographs range from 22 to 75 percent [8]. One meta-analysis including diabetic foot ulcers reported a pooled sensitivity and specificity of 0.54 and 0.68, respectively [9].

Radiographic findings of osteomyelitis include soft tissue swelling, osteopenia, cortical loss, bony destruction, and periosteal reaction [10-13]. Radiographs may be unremarkable for the first 10 to 14 days following infection [3]. Bony destructive changes on radiography lag at least two weeks behind clinical infection; approximately 50 to 75 percent of the bone matrix must be destroyed before plain radiographs demonstrate lytic changes [14].

Following trauma, radiographic findings of architectural distortion, osteopenia due to disuse, and normal fracture healing may be difficult to distinguish from osteomyelitis [15]. In addition, conventional radiography may be insufficient to distinguish osteomyelitis from other processes such as Charcot arthropathy and fracture [16].In the presence of orthopedic hardware, findings of osteomyelitis may include fracture, nonunion, or periprosthetic lucency. In the setting of chronic osteomyelitis, reactive sclerosis, sequestra, and involucrum may be observed [10,11].

Magnetic resonance imaging — Magnetic resonance imaging (MRI) has excellent sensitivity for diagnosis of osteomyelitis. After conventional radiographic evaluation, MRI is generally considered the study of choice for further assessment [4,5,17-20]. It is useful for obtaining images delineating the extent of cortical destruction characteristic of osteomyelitis, as well as to evaluate for presence of bone marrow abnormality, soft tissue inflammation (such as in the setting of cellulitis, myositis, and/or ulceration), and ischemia (picture 1) [21,22]. MRI may demonstrate abnormal marrow edema as early as one to five days following onset of infection [9,17,23]. Intravenous contrast does not improve the detection of osteomyelitis on MRI but does improve the distinction between phlegmon, necrotic tissue, and abscess.

MRI has high sensitivity and negative predictive value [1,4,9,24-26]. In one meta-analysis, the sensitivity of MRI was superior to conventional radiography and nuclear modalities (including bone scans and white blood cell studies) [24]. Another meta-analysis including patients with diabetic foot ulceration who underwent MRI reported a pooled sensitivity and specificity of 90 and 79 percent, respectively (image 4) [9]. A subsequent meta-analysis confirmed the high sensitivity of 93 percent but with a poorer specificity of 70 percent; technetium-99m hexamethylpropylene amine oxime (HMPAO)-tagged white blood cells and fluorine-18-fluorodeoxyglucose positron emission tomography (18F-FDG PET) had higher specificities [6]. Given the high negative predictive value of MRI, an MRI with no evidence of osteomyelitis is sufficient for exclusion of osteomyelitis if clinical signs or symptoms have been present for at least one week [1].

Both T1-weighted and fat-suppressed T2-weighted (or short tau inversion recovery) images should be obtained; these are usually performed in the same imaging plane, and multiple imaging planes are usually obtained. Abnormal osseous signal on all sequences in the region of concern in the correct clinical setting confirms the diagnosis of osteomyelitis. Soft tissue abnormalities adjacent to the bone and

https://www.uptodate.com/...rint?search=osteomyelitis&source=search_result&selectedTitle=3~150&usage_type=default&display_rank=3[19.03.2020 15:32:09] Approach to imaging modalities in the setting of suspected nonvertebral osteomyelitis - UpToDate

bony destruction increase diagnostic confidence [24]. Absence of osseous signal abnormality on all sequences excludes infection.

MRI may overestimate the extent and duration of infection, given its high sensitivity. Reactive marrow edema seen on fluid sensitive images may coexist with true marrow infection, leading to an imaging abnormality that is larger than the area of actual infection. However, the T1-weighted images likely underestimate the extent of disease. One study suggests that marked ischemia may affect the overall accuracy of MRI in detecting osteomyelitis [27]. Lastly, bone marrow changes may persist for weeks to months after osteomyelitis begins to respond to therapy.

Bone marrow signal abnormality on MRI is a nonspecific finding that can be seen with a variety of other pathologies including contusion, fracture, postsurgical change, arthritis, neoplasm, and Charcot arthropathy [28]. Establishing the correct diagnosis depends on the clinical setting and on additional imaging findings. Moreover, if infection coexists with additional pathology that can cause bone marrow edema, MRI cannot reliably distinguish between marrow changes attributable to infection and those attributable to other pathology.

It may be diagnostically challenging to distinguish a diabetic foot with Charcot arthropathy from concomitant infection on MRI. The presence of sinus tracts, fluid collections with thick rim or diffuse enhancement, and extensive adjacent marrow abnormality are concerning for Charcot with superimposed osteomyelitis [29]. In cases of severe Charcot arthropathy, definitive radiographic exclusion of osteomyelitis may not be possible. Preliminary data suggest that techniques such as diffusion weighted MRI may help in the differentiation of Charcot arthropathy from osteomyelitis [30].

MRI is the imaging modality of choice for delineating the anatomy of the spinal cord and adjacent osseous and soft tissues. (See "Vertebral osteomyelitis and discitis in adults".)

Gadolinium contrast-enhanced images are not required to diagnose acute osteomyelitis. However, the administration of contrast is useful to enhance visualization of sinus tracts, fistulas, and necrotic tissue and to distinguish between abscess and phlegmon (picture 1) [21,22]. The utility of gadolinium contrast- enhanced images is increased in chronic osteomyelitis as areas of active inflammation will enhance and abscesses are well demarcated [17].

The penumbra sign, a thin layer of granulation tissue lining a bone abscess cavity, may be seen in osteomyelitis (image 5). This finding produces a higher signal on T1-weighted magnetic resonance images; in one study, it had a sensitivity and specificity of 73 and 99 percent, respectively [31].

Metallic hardware can give rise to artifact that may degrade MRI image quality and limit diagnostic capability.

Computed tomography — Computed tomography (CT) is more sensitive than conventional radiography for assessing cortical and trabecular integrity, periosteal reaction, intraosseous gas, soft tissue gas, and the extent of sinus tracts (image 6) [12,15,17,32-35]. It is useful in chronic osteomyelitis and may be the most useful modality to evaluate for the presence of osseous sequestra and involucrum [1,20]. https://www.uptodate.com/...rint?search=osteomyelitis&source=search_result&selectedTitle=3~150&usage_type=default&display_rank=3[19.03.2020 15:32:09] Approach to imaging modalities in the setting of suspected nonvertebral osteomyelitis - UpToDate

Intravenous contrast is required for detection of soft tissue abnormalities such as sinus tracts. Noncontrast CT allows assessment of gas but does not evaluate soft tissue pathology as well as a contrasted CT.

Metallic hardware can give rise to artifact that may degrade CT image quality and limit diagnostic capability (image 7).

Nuclear modalities — A nuclear study may be useful if metal hardware precludes MRI or CT. Nuclear imaging has high sensitivity for detecting evidence of inflammation and therefore tends to be more reliable for evaluation of acute infection than chronic infection. There are a number of different nuclear study modalities, including positron emission tomography (PET) scans, three-phase bone scans, and tagged white blood cell (WBC) scans; gallium scans are used less often.

A major limitation of nuclear studies is that radiographic evidence of bone turnover or inflammation due to noninfectious bone pathology may be confused with osteomyelitis [36-39]. Such conditions include recent trauma or surgery, recently healed osteomyelitis, septic arthritis, degenerative joint disease, bone tumors, and Paget disease [40,41]. False-negative results are possible in areas of relative ischemia (a common comorbidity in osteomyelitis) since radiotracer may not be adequately delivered to the target site.

Flourine-18-labeled fluorodeoxyglucose (FDG) imaging using PET is a relatively new modality that has shown promising results for imaging of infection [4,42-45] and may overcome some of the limitations with other nuclear imaging studies.

● Positron emission tomography – 18F-FDG PET uses 18F-FDG, a glucose analog that accumulates in leukocytes, which in turn accumulate at the site of infection. The 18F-FDG molecule accumulates rapidly even in poorly perfused areas due to its small size [46]. As such, imaging is performed 30 to 60 minutes after tracer injection, making the study faster than other nuclear medicine studies [17]. The tracer provides high-resolution tomographic images and, when combined with CT (18F-FDG PET CT), provides the anatomic detail of conventional CT scans.

Data suggest that 18F-FDG PET is useful for assessing both acute and chronic osteomyelitis [26,46]. A meta-analysis including 299 patients from nine studies reported a pooled sensitivity and specificity of 74 and 91 percent, respectively [26]. A subsequent meta-analysis including more than 250 patients reported a sensitivity and specificity 89 and 92 percent, respectively [6]. A meta- analysis evaluating imaging modalities in patients with chronic osteomyelitis reported PET to be superior to other modalities (sensitivity and specificity of 96 and 91 percent, respectively) [47]. Preliminary data suggest 18F-FDG PET may be useful in distinguishing Charcot arthropathy from normal joints and patients with osteomyelitis [48]. 18F-FDG PET is useful in assessing peripheral post-traumatic osteomyelitis [49].

18F-FDG PET may be useful for diagnosing spondylodiscitis. (See "Vertebral osteomyelitis and discitis in adults".)

18F-FDG PET has several disadvantages; these include the inability to discriminate tumor from infection, high cost, false positives due to postsurgical inflammatory changes, and limited availability. Tissue inflammation associated with spinal hardware and spinal degenerative changes may be confounders [46]. As such, 18F-FDG PET may be useful as an alternative to MRI for circumstances in which MRI is contraindicated or as a supplement when MRI is equivocal.

● Three-phase bone scan – Three-phase bone scans use a radionuclide tracer that accumulates in areas of bone turnover and increased osteoblast activity (such as technetium-99m bound to a phosphorus-containing compound) [40]. The scans are performed using a gamma camera at three points following tracer injection: immediately after injection (blood flow phase), 15 minutes after injection (blood pool phase), and four hours after injection (osseous phase). In the setting of osteomyelitis, there is intense uptake in all three phases; in the setting of cellulitis, there is increased activity only in the first two phases and normal or mild diffuse increased activity in the third phase [12].

The sensitivity and specificity of three-phase bone scan for detection of osteomyelitis varies depending on the appearance of correlative radiographs. If conventional radiographs are normal, three-phase bone scan has a sensitivity and specificity of about 95 percent [1,40,50]. If radiographs demonstrate noninfectious disorders such as fracture or Charcot arthropathy, (entities associated with bone formation and radionuclide tracer uptake), false-positive results are more likely. False- negative results are possible in early osteomyelitis or in the setting of chronic osteomyelitis with impaired blood flow or infarction [41]. In one meta-analysis, the pooled sensitivity and specificity for three-phase bone scans were 0.81 and 0.28, respectively [9].

● Tagged white blood cell scan – A tagged WBC scan uses autologous WBCs and requires a circulating WBC of at least 2000 per microliter [19]. The WBCs are labeled with indium 111 oxyquinoline, gallium-67, or technetium-99m [1]. To perform the study, blood is drawn from the patient, and the white blood cells are separated for labeling with tracer; after a few hours, the tagged white cells are returned to the patient's circulation via intravenous injection. The time of imaging is dependent upon the isotope used. For technetium-99m, imaging begins four to six hours after administration and may be repeated at 18 and 30 hours. For indium-111, images are acquired 18 to 30 hours following injection [17]. Images are taken up to 24 hours later. The tagged white cells accumulate in the bone marrow and at sites of inflammation or infection; they are not specific for bone. The different tagging agents result in different advantages and disadvantages for the agent used. For example, indium 111-labeled WBCs are more stable than those tagged with technetium 99m, but the scans are of much lower resolution [46].

Tagged WBC scans have similar sensitivity to bone scans for evaluation of osteomyelitis [51]. Reported sensitivities and specificities range from 72 to 100 percent and 67 to 100 percent, respectively [46]. In a meta-analysis comprising 206 patients undergoing indium-111 WBC scintigraphy, a 92 percent sensitivity and 75 percent specificity were reported. In the same meta- analysis, using technetium-99m HMPAO in 406 patients, the specificity improved to 92 percent with https://www.uptodate.com/...rint?search=osteomyelitis&source=search_result&selectedTitle=3~150&usage_type=default&display_rank=3[19.03.2020 15:32:09] Approach to imaging modalities in the setting of suspected nonvertebral osteomyelitis - UpToDate

a sensitivity of 91 percent [6]. Despite these results, it has been reported that specificity can be poor if corresponding radiographs are not normal [51]. In addition, regions with substantial quantities of red marrow (such as the vertebral bodies) are not visualized reliably with this modality; WBC scans may best be used in the distal extremities [41]. Although studies suggest that when combined with bone scintigraphy, technetium-99m HMPAO is useful in patients with Charcot arthropathy, tagged WBC scans can be falsely positive in the setting of other causes of inflammation including fracture [52]. False-negative results are possible in the setting of chronic osteomyelitis when white cell migration to sites of infection is decreased.

● Gallium and dual tracer scans – Gallium scans utilize the affinity of gallium-67 to acute phase reactants (lactoferrin, transferrin, and others) to demonstrate areas of inflammation that may be related to infection [51]. This older modality is used less commonly than the other nuclear modalities described above [46].

This method is quite sensitive and more specific than three-phase bone scan (sensitivity and specificity 25 to 80 and 67 percent, respectively) [53,54]. If negative, gallium scans effectively exclude the diagnosis of osteomyelitis [1]. False-positive results can occur in the setting of uptake related to fracture and neoplasm; correlative radiographs may help to evaluate for these entities. At present, gallium imaging is limited primarily to the spine [46].

Scanning is typically performed 18 to 72 hours following gallium injection and therefore should be reserved for patients who are clinically stable and do not require prompt imaging results for urgent management decisions [17].

A gallium scan can be performed concurrently with a technetium-labeled three-phase bone scan, and the information gathered may be more useful than that obtained from either examination alone [54]. In this instance, both radionuclide species are injected at the same time. Then, bone scan images can be obtained three to four hours after injection, and gallium scan images can be obtained up to 24 hours later. The result is considered positive when gallium tracer uptake is greater than that of the bone scan.

● SPECT-CT – Single photon emission CT (SPECT-CT) has been shown to increase the accuracy of gallium studies, tagged WBC studies, and three-phase bone scans. Improved localization of the site of osteomyelitis and, more importantly, improved distinction between soft tissue infection and osteomyelitis have been reported [55]. The use of SPECT-CT has also shown to improve the accuracy of tagged WBC studies in post-traumatic osteomyelitis [49]. CT has been shown to increase the accuracy of gallium studies, tagged WBC studies, and three-phase bone scans. This tool allows improved distinction between soft tissue infection and osteomyelitis as well as improved localization of osteomyelitis [55].

Ultrasonography — Ultrasound may be a useful diagnostic tool for circumstances in which other modalities are not readily available. Typically, bone is not well depicted by ultrasound, because the

cortical surface of the bone reflects the acoustic energy that is used to generate ultrasound images. However, changes superficial to cortical bone can be visualized by ultrasound.

In osteomyelitis, ultrasound can demonstrate elevation and/or thickening of the periosteum due to pus emanating from the bone [56-58]. Ultrasound may be more useful for detection of these findings in pediatric patients, since the periosteum in the pediatric skeleton is more loosely adherent to the cortex than in the adult skeleton [1,17]. Ultrasonography is considered excellent for aspirating suspected infected fluid collections or abscesses [59]. (See "Overview of the clinical manifestations of sickle cell disease" and "Hematogenous osteomyelitis in children: Evaluation and diagnosis", section on 'Ultrasonography'.)

SOCIETY GUIDELINE LINKS

Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Osteomyelitis and prosthetic joint infection in adults".)

SUMMARY

● In general, if osteomyelitis is suspected based on clinical history and physical findings, imaging should begin with conventional radiographs of the involved area for patients with at least two weeks of clinical symptoms. A more sophisticated imaging modality should be pursued for patients with less than two weeks of symptoms, normal radiographs, or radiographs suggestive of osteomyelitis without definitive characteristic features. In general, magnetic resonance imaging (MRI) is the imaging modality with greatest sensitivity for diagnosis of osteomyelitis; if MRI is not available or contraindicated, computed tomography (CT) is an appropriate alternative test. If metal hardware precludes MRI or CT, a nuclear study is appropriate. (See 'Selecting an imaging modality' above and "Osteomyelitis in adults: Clinical manifestations and diagnosis", section on 'Clinical approach'.)

● In the setting of osteomyelitis, inflammatory exudate in the marrow causes elevated medullary pressure, which compresses vascular channels, leading to ischemia and bone necrosis. If the areas of necrotic bone separate from the remaining viable bone, sequestra are formed. Surviving bone and periosteum ultimately produce a sheath of bone surrounding the area of necrosis, which is referred to as an involucrum. Both the sequestra and involucrum may be apparent radiographically. (See 'Pathophysiology of osteomyelitis' above.)

● Findings of osteomyelitis on conventional radiography include osteopenia, cortical loss, bony destruction, and periosteal reaction. Other chronic findings include reactive sclerosis, sequestra, and involucrum. Conventional radiographs are useful for identification of noninfectious pathology and for identifying air within soft tissues. However, conventional radiography may be insufficient to distinguish osteomyelitis from other processes such as Charcot arthropathy and fracture. (See https://www.uptodate.com/...rint?search=osteomyelitis&source=search_result&selectedTitle=3~150&usage_type=default&display_rank=3[19.03.2020 15:32:09] Approach to imaging modalities in the setting of suspected nonvertebral osteomyelitis - UpToDate

'Conventional radiography' above.)

● MRI has high sensitivity and negative predictive value for diagnosis of osteomyelitis. MRI may demonstrate abnormal marrow edema as early as one to five days following onset of infection, and an MRI with no evidence of osteomyelitis is sufficient for exclusion of osteomyelitis in patients with symptoms for at least one week. MRI is useful for delineating the extent of cortical destruction characteristic of osteomyelitis, as well as for detecting presence of bone marrow and soft tissue inflammation (such as in the setting of cellulitis, myositis, and/or ulceration). However, MRI may overestimate the extent and duration of infection and cannot reliably distinguish between marrow changes attributable to infection and those attributable to other pathology. Intravenous gadolinium contrast does not improve the detection of acute osteomyelitis but does improve the distinction between phlegmon, necrotic tissue, and abscess. (See 'Magnetic resonance imaging' above.)

● CT is more sensitive than conventional radiography for assessing cortical and trabecular integrity, periosteal reaction, intraosseous gas, soft tissue gas, and the extent of sinus tracts. It is the most useful modality to evaluate for the presence of osseous sequestra and involucrum. (See 'Computed tomography' above.)

● A nuclear study may be useful if metal hardware precludes MRI or CT. Nuclear imaging has high sensitivity for detecting evidence of inflammation and therefore tends to be more reliable for evaluation of acute infection than chronic infection. However, a major limitation is that radiographic evidence of bone turnover or inflammation due to noninfectious bone pathology may be confused with osteomyelitis. Single photon emission CT (SPECT-CT) has been shown to improve the accuracy of tracer imaging alone. While fluorine-18-fluorodeoxyglucose positron emission tomography CT may provide similar diagnostic accuracy as MRI, its high cost and lack of insurer reimbursement preclude routine use. Tagged white blood cell studies combined with three-phase bone scan or SPECT-CT are more practical choices. Single photon emission CT improves the accuracy of tracer imaging alone. (See 'Nuclear modalities' above.)

● Ultrasound may be a useful diagnostic tool in circumstances where the more preferred modalities are not readily available. This may be especially true in the pediatric population. In addition, ultrasound is excellent for aspirating suspected infected fluid collections or abscesses. (See 'Ultrasonography' above.)

ACKNOWLEDGMENT

The editorial staff at UpToDate would like to acknowledge Dr. Perry Horwich and Dr. Mary Hochman, who contributed to earlier versions of this topic review.

Use of UpToDate is subject to the Subscription and License Agreement.

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48. Basu S, Chryssikos T, Houseni M, et al. Potential role of FDG PET in the setting of diabetic neuro- osteoarthropathy: can it differentiate uncomplicated Charcot's neuroarthropathy from osteomyelitis and soft-tissue infection? Nucl Med Commun 2007; 28:465.

49. Govaert GA, IJpma FF, McNally M, et al. Accuracy of diagnostic imaging modalities for peripheral post-traumatic osteomyelitis - a systematic review of the recent literature. Eur J Nucl Med Mol Imaging 2017; 44:1393.

50. Schauwecker DS. The role of nuclear medicine in osteomyelitis. In: Skeletal Nuclear Medicine, Colli er DB, et al (Eds), Mosby, St. Louis 1996.

51. Thrall J, Ziessman H. Nuclear Medicine: The Requisites, 2nd ed, Mosby, St. Louis 2001.

52. Poirier JY, Garin E, Derrien C, et al. Diagnosis of osteomyelitis in the diabetic foot with a 99mTc- HMPAO leucocyte scintigraphy combined with a 99mTc-MDP bone scintigraphy. Diabetes Metab 2002; 28:485.

53. Palestro CJ, Kim CK, Swyer AJ, et al. Radionuclide diagnosis of vertebral osteomyelitis: indium- 111-leukocyte and technetium-99m-methylene diphosphonate bone scintigraphy. J Nucl Med 1991; 32:1861.

54. Tumeh SS, Aliabadi P, Weissman BN, McNeil BJ. Chronic osteomyelitis: bone and gallium scan patterns associated with active disease. Radiology 1986; 158:685.

55. Saha S, Burke C, Desai A, et al. SPECT-CT: applications in musculoskeletal radiology. Br J Radiol 2013; 86:20120519.

56. Abiri MM, Kirpekar M, Ablow RC. Osteomyelitis: detection with US. Radiology 1989; 172:509.

57. Howard CB, Einhorn M, Dagan R, Nyska M. Ultrasound in diagnosis and management of acute haematogenous osteomyelitis in children. J Bone Joint Surg Br 1993; 75:79.

58. Wheat J. Diagnostic strategies in osteomyelitis. Am J Med 1985; 78:218.

59. Booz MM, Hariharan V, Aradi AJ, Malki AA. The value of ultrasound and aspiration in differentiating vaso-occlusive crisis and osteomyelitis in sickle cell disease patients. Clin Radiol 1999; 54:636.

Topic 7653 Version 22.0

GRAPHICS

Summary statistics of imaging modalities for diagnosis of osteomyelitis associated with diabetic foot ulcer

Sensitivity Specificity Total Diagnostic modality (95% confidence (95% confidence Study patients interval) interval)

Probe-to-bone test or 288 0.60 (0.46-0.73) 0.91 (0.86-0.94) Dinh et exposed bone al

Radiography 177 0.54 (0.44-0.63) 0.68 (0.53-0.80) Dinh et al

Magnetic resonance imaging 135 0.90 (0.82-0.95) 0.79 (0.62-0.91) Dinh et 421 0.93 (0.82-0.97) 0.75 (0.63-0.84) al Lauri et al

Bone scan 185 0.81 (0.73-0.87) 0.28 (0.17-0.42) Dinh et al

Leukocyte scan 269 0.74 (0.67-0.80) 0.68 (0.57-0.78) Dinh et al

In-111 oxine WBC 206 0.92 (0.72-0.98) 0.75 (0.66-0.82) Lauri et al

Tc-99m HMPAO WBC 406 0.91 (0.86-0.94) 0.92 (0.78-0.98) Lauri et al

18F-FDG PET/CT 254 0.89 (0.68-0.97) 0.92 (0.85-0.96) Lauri et al

WBC: white blood cell; HMPAO: hexamethylpropyleneamine oxime; 18F-FDG PET/CT: 18F-labeled fluoro-2-deoxyglucose positron emission tomography/computed tomography.

Data reproduced with permission from: Dinh MT, Abad CL, Safdar N. Diagnostic accuracy of the physical examination and imaging tests for osteomyelitis underlying diabetic foot ulcers: Meta-analysis. Clin Infect Dis 2008; 47:519-527. Copyright © 2008 University of Chicago Press. With additional data from: 1. Lauri C, Tamminga M, Glaudemans AWJM. Detection of Osteomyelitis in the Diabetic Foot by Imaging Techniques: A systematic Review and Meta-analysis Comparing MRI, White Blood Cell Scintigraphy, and FDG-PET. Diabetes Care 2017; 40: 1111-1120.

Graphic 61072 Version 5.0

Adult with chronic osteomyelitis

39-year-old man with chronic osteomyelitis of the tibia and a draining wound. Plain films (A and B) demonstrate a sclerotic sequestrum in the defect of the tibia (arrow). Magnetic resonance imaging axial T1 & T2 images (C and D) show the sequestrum (arrow) in the intraosseous abscess. The abscess/sinus tract can be seen extending to the skin on the T2 image (arrowhead).

Courtesy of Charles Spritzer, MD.

Graphic 107686 Version 1.0

Child with chronic osteomyelitis

Four-year-old boy with chronic osteomyelitis. Radiographs of the femur demonstrate pathologic fracture and involucrum (arrow).

Courtesy of Charles Spritzer, MD.

Graphic 107687 Version 1.0

Osteomyelitis of the toe

Radiograph of the foot demonstrates air in the soft tissues about the 5th toe (black arrowheads). Cortical destruction of the 5th metatarsal head is also seen (white arrow). Irregular contour of the overlying skin represents associated soft tissue ulceration (asterisk).

Courtesy of Perry Horwich, MD.

Graphic 82657 Version 2.0

Osteomyelitis of the patella

(A) Axial T1-weighted image demonstrates signal changes and cortical interruption overlying the anterior and lateral patella. Patellar osteomyelitis is present (long arrow). Incidental note is made of an enchondroma (asterisk). (B) Axial short tau inversion recovery (STIR) image demonstrates high signal edema in the marrow of the anterior and lateral patella with overlying soft tissue loss representing osteomyelitis (long arrow). A small knee joint effusion is also present (arrowheads). (C,D) Pre- and postcontrast axial images demonstrate enhancement in the distribution of edema in the patella and overlying soft tissues. Patellar osteomyelitis is present in panel D (long arrow).

Courtesy of Perry Horwich, MD.

Graphic 80488 Version 3.0

Osteomyelitis in the setting of a diabetic foot ulcer

(A) Sagittal fluid-sensitive short inversion time inversion recovery (STIR) image demonstrates high signal fluid collection along the plantar surface of the calcaneus (arrow). (B) Sagittal post-contrast T1-weighted image with fat saturation demonstrates the peripherally enhancing fluid collection (arrow). (C) Sagittal T1-weighted pre-contrast image demonstrates some cortical interruption (arrow). (D) Lateral radiograph demonstrates soft tissue loss overlying the plantar aspect of the calcaneus (arrow). Osseous remodeling and periosteal reaction about the posterior calcaneus (asterisk) reflect changes associated with longstanding chronic osteomyelitis.

Courtesy of Perry Horwich, MD.

Graphic 57504 Version 6.0

Penumbra sign in osteomyelitis

Magnetic resonance imaging (MRI) scan shows the penumbra sign (a transitional zone with relatively high signal intensity between abscess and sclerotic bone marrow on T1-weighted MRI).

Graphic 56913 Version 11.0

Osteomyelitis in the heel

(A) Sagittal computed tomography image demonstrates cortical fragmentation of the plantar aspect of the calcaneus (arrows) and adjacent air and soft tissue ulceration. (B) Corresponding fluid-sensitive short inversion time inversion recovery (STIR) image demonstrates extensive high-signal edema in the calcaneus (asterisk) and again demonstrates posterior plantar ulcer overlying the calcaneus (arrow).

Courtesy of Perry Horwich, MD.

Graphic 78389 Version 7.0

Osteomyelitis in the setting of hip prosthesis

(A) Coronal-reformatted computed tomography image demonstrates marked beam hardening artifact about a metallic left hip prosthesis (arrow). (B) Despite extensive artifact in image A, on lung windows, a region of air can be identified adjacent to the lesser trochanter (arrow). (C) Fluoroscopic-guided aspiration (arrow indicates needle) yielded 3 cc of pus. Initial Gram stain was positive for gram-negative rods; cultures subsequently grew Bacteroides fragilis.

Courtesy of Perry Horwich, MD.

Graphic 67235 Version 4.0

Contributor Disclosures

Charles E Spritzer, MD Nothing to disclose Denis Spelman, MBBS, FRACP, FRCPA, MPH Nothing to disclose Elinor L Baron, MD, DTMH Nothing to disclose

Conflict of interest policy

Contributor Disclosures

Charles E Spritzer, MD Nothing to disclose Denis Spelman, MBBS, FRACP, FRCPA, MPH Nothing to disclose Elinor L Baron, MD, DTMH Nothing to disclose

Conflict of interest policy

https://www.uptodate.com/...rint?search=osteomyelitis&source=search_result&selectedTitle=3~150&usage_type=default&display_rank=3[19.03.2020 15:32:09] Hematogenous osteomyelitis in children: Epidemiology, pathogenesis, and microbiology - UpToDate

Official reprint from UpToDate® www.uptodate.com ©2020 UpToDate, Inc. and/or its affiliates. All Rights Reserved. Print Options Print | Back Text References Graphics Hematogenous osteomyelitis in children: Epidemiology,Contributor Disclosures pathogenesis, and microbiology

Author: Paul Krogstad, MD Section Editors: Sheldon L Kaplan, MD, William A Phillips, MD Deputy Editor: Mary M Torchia, MD

All topics are updated as new evidence becomes available and our peer review process is complete.

Literature review current through: Feb 2020. | This topic last updated: Nov 18, 2019.

INTRODUCTION

Osteomyelitis is an infection localized to bone. It is usually caused by microorganisms (predominantly bacteria) that enter the bone hematogenously. Other pathogenic mechanisms include direct inoculation (usually traumatic, but also surgical) or local invasion from a contiguous infection (eg, cellulitis, sinusitis, periodontal disease). Other risk factors for nonhematogenous osteomyelitis include open fractures that require surgical reduction, implanted orthopedic hardware (such as pins or screws), and puncture wounds.

The epidemiology, pathogenesis, and microbiology of hematogenous osteomyelitis in children will be discussed here. The clinical features, evaluation, diagnosis, and management of osteomyelitis in children are discussed separately:

● (See "Hematogenous osteomyelitis in children: Clinical features and complications".) ● (See "Hematogenous osteomyelitis in children: Evaluation and diagnosis".) ● (See "Hematogenous osteomyelitis in children: Management".)

EPIDEMIOLOGY

The incidence of osteomyelitis varies geographically. As summarized in a 2012 systematic review and meta-analysis that included >12,000 patients, the incidence ranged from approximately 1 in 5000 to 7700 children in developed countries and 1 in 500 to 2300 children in developing countries [1]. Some countries have noted a decrease in the incidence over time [2], whereas others, including the United States, have noted an increase, particularly with the emergence of community-associated methicillin-resistant Staphylococcus aureus [3,4].

Hematogenous osteomyelitis is more common in children than in adults. Boys are affected nearly twice https://www.uptodate.com/...rint?search=osteomyelitis&source=search_result&selectedTitle=6~150&usage_type=default&display_rank=6[19.03.2020 15:28:37] Hematogenous osteomyelitis in children: Epidemiology, pathogenesis, and microbiology - UpToDate

as often as girls [1]. More than one-half of pediatric cases occur in children younger than five years and one-quarter in children younger than two years [5]. However, osteomyelitis is uncommon in young infants (<4 months) without underlying risk factors [6]. (See 'Risk factors' below.)

RISK FACTORS

Risk factors for osteomyelitis in neonates (<30 days of age) include [6-8]:

● Complicated delivery ● Prematurity ● Skin infection ● Central venous catheter ● Urinary tract anomalies ● Active maternal infection at the time of delivery [9]

Risk factors for hematogenous osteomyelitis in older infants and children include:

● Sickle cell disease (see "Acute and chronic bone complications of sickle cell disease", section on 'Osteomyelitis and septic arthritis')

● Immunodeficiency disorders, such as chronic granulomatous disease (see "Chronic granulomatous disease: Pathogenesis, clinical manifestations, and diagnosis", section on 'Infections')

● Sepsis

● Minor trauma coincident with bacteremia

● Indwelling vascular catheters, including hemodialysis catheters

PATHOGENESIS

Overview — Hematogenous osteomyelitis in long (tubular) bones begins with bacterial deposition in the metaphysis (figure 1). The mechanism of deposition is unclear, although some evidence suggests that endothelial cells permit microbial passage [10-12]. Trauma or emboli may cause occlusion of the slow- flowing sinusoidal vessels, further establishing a nidus for infection.

The focus of infection in the metaphysis leads to cellulitis in the bone marrow. Inflammatory exudate in the marrow causes increased intramedullary pressure, which forces the exudate through the Haversian systems and Volkmann canals and into the cortex, where it can rupture through the periosteum. Areas of bone necrosis may develop at foci of infection within the bone. The resulting devitalized bone (known as a sequestrum) can be visualized radiographically and may be surrounded by new bone laid down by the elevated periosteum (known as the involucrum). Infection can spread to the epiphysis and adjacent joint space; contiguous extension into the joint space occurs in as many as one-third of cases overall [1,9,13- https://www.uptodate.com/...rint?search=osteomyelitis&source=search_result&selectedTitle=6~150&usage_type=default&display_rank=6[19.03.2020 15:28:37] Hematogenous osteomyelitis in children: Epidemiology, pathogenesis, and microbiology - UpToDate

15].

Subacute/chronic osteomyelitis is sometimes associated with the formation of an intraosseous abscess (Brodie abscess), a central area of suppuration and necrosis contained and encapsulated by granulation tissue and sclerosis (image 1) [16,17]. (See "Osteomyelitis in adults: Clinical manifestations and diagnosis", section on 'Hematogenous osteomyelitis'.)

Age-specific features — The pathogenesis of osteomyelitis in children is influenced by characteristics of the growing skeleton (figure 2) [18].

Birth to three months — Three features of the young infant skeleton facilitate the spread of bone infection [18]:

● The thin cortex and loosely applied periosteum are poorly able to contain infection, which can extend along the subperiosteal space and break through into the surrounding soft tissue

● Nutrient metaphyseal capillaries perforate the epiphyseal growth plate, particularly in the hip, shoulder, and knee; these capillaries may permit spread of infection to the epiphysis and joint surface, causing concomitant septic arthritis

● The capsule of the diarthrodial joints frequently extends to, or is slightly distal to, the epiphyseal plate, allowing infection to invade the joint space and causing concomitant septic arthritis from a focus of osteomyelitis either proximal or distal to the joint (see "Bacterial arthritis: Epidemiology, pathogenesis, and microbiology in infants and children", section on 'Pathogenesis')

Older infants and toddlers — The developing skeleton in older infants and toddlers is better able to contain bone infection:

● As the skeleton matures, the cortex becomes thicker and the periosteum slightly more dense. Infection rarely spreads to the soft tissues, but subperiosteal abscess and contiguous edema readily develop; subperiosteal abscess typically occurs at the metaphysis, where the cortex is the thinnest [19].

● Metaphyseal capillaries atrophy as the epiphysis becomes ossified and a distinct physeal plate is formed. This process begins as early as eight months of age, is usually complete by 18 months, and has traditionally been considered to limit the spread of infection to the joint space [20], unless the metaphysis is intracapsular, as it is in the shoulder, ankle, hip, and elbow. However, concurrent septic arthritis and osteomyelitis are now commonly encountered [21,22], and transphyseal vessels are of unclear importance.

Older children and adolescents — In older children and adolescents, the metaphyseal cortex is considerably thicker, with a dense, fibrous periosteum. These features help to contain the infection, which rarely ruptures to spread to the outer cortex. In adolescents, this may result in an intraosseous abscess in which a central area of suppuration and necrosis is contained and encapsulated by granulation tissue

https://www.uptodate.com/...rint?search=osteomyelitis&source=search_result&selectedTitle=6~150&usage_type=default&display_rank=6[19.03.2020 15:28:37] Hematogenous osteomyelitis in children: Epidemiology, pathogenesis, and microbiology - UpToDate

(Brodie abscess (image 1)). (See "Osteomyelitis in adults: Clinical manifestations and diagnosis", section on 'Hematogenous osteomyelitis'.)

Vertebral osteomyelitis — Vertebral infections can involve either the intervertebral disc (discitis) or the vertebral body. In young children, the blood supply to the intervertebral disc is rich, derived from periosteal vessels and adjacent vertebral bodies. The vessels from adjacent vertebrae begin to atrophy in the first year of life and are obliterated completely by 10 years of age [23,24]. This may account for the observation that discitis is more common in younger children [25]. (See "Hematogenous osteomyelitis in children: Clinical features and complications", section on 'Spine'.)

The pathogenesis of vertebral osteomyelitis may be related to sluggish blood flow and thrombosis in the vertebral veins. It is discussed separately. (See "Vertebral osteomyelitis and discitis in adults", section on 'Pathogenesis'.)

MICROBIOLOGY

Most cases of acute hematogenous osteomyelitis in children are caused by gram-positive bacteria, principally S. aureus (table 1) [1]. However, no pathogen is isolated in routine cultures of blood and wound aspirates in up to one-half of cases [1], which usually are presumed to be caused by S. aureus and treated accordingly [26,27]. In younger children, many of these may actually be due to Kingella kingae. (See 'Kingella kingae' below and "Hematogenous osteomyelitis in children: Management", section on 'Culture-negative osteomyelitis'.)

Most cases of acute hematogenous osteomyelitis are caused by a single organism. Polymicrobial infections usually are associated with contiguous spread, trauma, vascular insufficiency, or immobility of an extremity. (See 'Polymicrobial infections' below.)

Staphylococcus — S. aureus is the most common cause of osteomyelitis in children overall. In a 2012 systematic review, it was identified in approximately two-thirds of cases occurring since 1996 [1]. The high frequency of S. aureus may be related to a number of extracellular and cell-associated virulence factors that promote bacterial adherence, resistance to host defense mechanisms, and proteolytic activity.

Although the prevalence of community-associated methicillin-resistant S. aureus (CA-MRSA) varies geographically, it is an important cause of pediatric musculoskeletal infections. CA-MRSA is associated with more severe infection than methicillin-susceptible S. aureus (MSSA) [28-30]. In a retrospective review of 59 children with S. aureus osteomyelitis evaluated at a single center between 2000 and 2002, CA-MRSA was identified from blood or bone cultures in 31 individuals (53 percent) [31]. PVL positivity was more frequent in MRSA than MSSA isolates (87 versus 24 percent), and all children who developed complications had PVL-positive isolates. However, in a more recent review of 287 children with S. aureus acute hematogenous osteoarticular infections from the same institution, agr group III S. aureus was associated with increased risk of orthopedic complications (22 versus 9 percent), while PVL positivity was

not a predictor [22]. Additional reports also suggest that multifocal disease, local abscess formation, venous thrombosis, and a greater systemic inflammatory response are more common with PVL-positive isolates [32-36]. However, osteomyelitis, pneumonia, and other severe manifestations can be demonstrated in the absence of PVL, likely reflecting the presence of multiple virulence factors elaborated by S. aureus, particularly the USA300 strains that now predominate in the United States [32- 36]. (See "Methicillin-resistant Staphylococcus aureus infections in children: Epidemiology and clinical spectrum", section on 'CA-MRSA strains'.)

Coagulase-negative staphylococci may cause osteomyelitis in neonates and children with indwelling vascular catheters (eg, for chronic hemodialysis). (See "Hematogenous osteomyelitis in children: Clinical features and complications", section on 'Chronic hemodialysis'.)

Groups A and B streptococci — Group A beta-hemolytic Streptococcus (Streptococcus pyogenes) may cause osteomyelitis in older infants and children, particularly as a complication of varicella-zoster virus infection [37]. In a 2012 systematic review, group A beta-hemolytic Streptococcus was identified in approximately 8 percent of cases occurring after 1996 [1].

Group B Streptococcus causes osteomyelitis in infants younger than three months. In a 2012 systematic review, group B Streptococcus was identified in approximately 4 percent of cases occurring after 1996 [1]. Infants with group B streptococcal osteomyelitis are usually two to four weeks of age. Generally, there is no recognized preceding infection and a single bone is involved. (See "Group B streptococcal infection in neonates and young infants", section on 'Other focal infection'.)

Streptococcus pneumoniae — Streptococcus pneumoniae (pneumococcus) may cause osteomyelitis in children who are at increased risk of invasive pneumococcal disease (eg, those with chronic heart disease, chronic lung disease, diabetes mellitus, sickle cell disease, asplenia, splenic dysfunction, immunodeficiency), including children younger than two years who are incompletely immunized against S. pneumoniae. However, in the post-pneumococcal conjugate vaccine era, most cases occur in children without risk factors and are caused by serotypes not included in the 13-valent pneumococcal conjugate vaccine (especially 35B and 33F) [38].

Kingella kingae — K. kingae, a gram-negative organism present in oral microbiome, is being increasingly identified as a cause of osteomyelitis in children 6 to 36 months of age [9,39-42], and some reports suggest K. kingae is the most common cause of osteomyelitis in Switzerland and France [9,42- 44]. It often affects nontubular bones (eg, sternum, vertebrae, calcaneum) [40].

K. kingae is a fastidious organism that is difficult to isolate by conventional culture techniques. Inoculation of specimens into blood culture vials and, especially, molecular diagnostic methods (eg, polymerase chain reaction amplification) may increase detection [40-42,45].

The epidemiology of skeletal infections caused by K. kingae was described in a cluster of cases in children attending a day care center [46]. Within a one-week period, three children aged 17 to 21 months attending the same classroom developed hematogenous osteomyelitis and septic arthritis. Child-to-child

transmission was supported by identical patterns on pulse field gel electrophoresis and the increased prevalence of nasal carriage among children in the index classroom compared with children in other classrooms (45 versus 7 percent).

Escherichia coli and other coliforms — E. coli and other coliforms can cause osteomyelitis in neonates. In a 2012 systematic review, E. coli was identified in approximately 2 percent of cases occurring after 1996 [1].

Haemophilus influenzae — Haemophilus influenzae type b (Hib) is a rare cause of osteomyelitis now that infants are routinely vaccinated against Hib [3,47,48].

Other bacteria — Other bacteria that can cause osteomyelitis include:

● Bartonella henselae osteomyelitis may occur in children with cat scratch disease [49-52]. In a literature review of 64 cases of B. henselae osteomyelitis, the vertebral column and pelvic girdle were the most frequent sites of infection; approximately one-third of patients had multifocal disease, with involvement of ≥3 bones [52]. (See "Microbiology, epidemiology, clinical manifestations, and diagnosis of cat scratch disease".)

● Pseudomonas aeruginosa is a cause of osteomyelitis in injection drug users. It also may occur in children with nail puncture wounds to the foot. (See "Pseudomonas aeruginosa skin and soft tissue infections", section on 'Infection following nail puncture'.)

● Brucella osteomyelitis may occur in children with travel to or living in an endemic area and in children who ingest unpasteurized dairy products. Brucella can produce abscesses in the vertebral bodies or long bones, although bone involvement is not a striking feature of the disease. (See "Brucellosis: Epidemiology, microbiology, clinical manifestations, and diagnosis".)

● Mycobacterium tuberculosis and nontuberculous mycobacteria can cause hematogenous osteomyelitis in children with immunodeficiency, penetrating injuries, or surgical history. (See "Skeletal tuberculosis" and "Epidemiology, clinical manifestations, and diagnosis of osteomyelitis due to nontuberculous mycobacteria" and "Treatment of osteomyelitis due to nontuberculous mycobacteria in adults".)

● Salmonella species – Salmonella species may cause osteomyelitis in children with sickle cell disease or related hemoglobinopathies, exposure to reptiles or amphibians, gastrointestinal symptoms, and children in developing countries.

● Actinomyces may cause osteomyelitis in facial bones or vertebral bodies [53]. (See "Cervicofacial actinomycosis".)

● Anaerobic organisms rarely cause osteomyelitis, which most often results from spread of infection from the paranasal sinuses (eg, Pott puffy tumor) or devitalized tissue. However, primary Fusobacterium osteomyelitis with concomitant septic arthritis has been described [54,55].

Fungi — Coccidiomycosis, which is increasingly common in the southwestern United States, can cause infection in cancellous bone such as vertebral bodies, distal tubular bones, and the skull [56]. Infection in multiple sites occurs in nearly one-half of all children and adults with musculoskeletal coccidioidomycosis [57-59]. (See "Manifestations and treatment of nonmeningeal extrathoracic coccidioidomycosis", section on 'Clinical manifestations'.)

Bone disease caused by Aspergillus has been described in immunocompetent individuals [60]. Aspergillus is frequently a cause of osteomyelitis in patients with chronic granulomatous disease [61].

Polymicrobial infections — Polymicrobial infection is unusual in children with acute osteomyelitis [62]. Isolation of multiple bacteria from bone generally occurs with spread from a contiguous infectious focus, usually from the skull, face, hands, or feet. Distal extremities that are compromised by vascular insufficiency or are immobile, as in patients with paraplegia, spina bifida, or following trauma such as lawn mower injuries, can be sites of polymicrobial osteomyelitis.

Pathogens in abnormal hosts

● Sickle cell disease – Among patients with sickle cell disease, hematogenous osteomyelitis is most often caused by Salmonella species or other gram-negative organisms, such as E. coli [63-70]. S. aureus, the most common cause of osteomyelitis in normal hosts, probably accounts for only one- fourth of all cases in sickle cell disease. (See "Acute and chronic bone complications of sickle cell disease".)

● Chronic granulomatous disease – Children with chronic granulomatous disease most often develop osteomyelitis caused by Serratia and Aspergillus species. Osteomyelitis is less often attributed to staphylococci, Pseudomonas, Burkholderia, Nocardia, and other bacterial and fungal species. (See "Chronic granulomatous disease: Pathogenesis, clinical manifestations, and diagnosis", section on 'Infections'.)

● HIV – Osteomyelitis in patients with human HIV infection is most commonly caused by S. aureus. S. pneumoniae infections are also particularly common in HIV-infected children who have not been immunized [71]. Other organisms that have been recovered in individual cases include E. coli, Salmonella enteritidis, Cryptococcus neoformans, Mycobacterium kansasii, and Histoplasma capsulatum.

SOCIETY GUIDELINE LINKS

Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Septic arthritis and osteomyelitis in children".)

SUMMARY https://www.uptodate.com/...rint?search=osteomyelitis&source=search_result&selectedTitle=6~150&usage_type=default&display_rank=6[19.03.2020 15:28:37] Hematogenous osteomyelitis in children: Epidemiology, pathogenesis, and microbiology - UpToDate

● The incidence of pediatric osteomyelitis varies geographically and is greater in developing than developed countries. Most cases occur in children younger than five years. Boys are affected approximately twice as often as girls. (See 'Epidemiology' above.)

● Risk factors for osteomyelitis in neonates include complicated delivery, prematurity, skin infection, central venous catheter, and urinary tract anomalies. Risk factors for osteomyelitis in older infants and children include sickle cell disease, immunodeficiency, sepsis, minor trauma with coincident bacteremia, and indwelling vascular catheter (including hemodialysis catheters). (See 'Risk factors' above.)

● The pathogenesis of hematogenous osteomyelitis involves deposition of bacteria in the metaphysis (from the metaphyseal vessels) leading to cellulitis of the bone marrow; the exudate under pressure is forced into the bony cortex, where it can lift or rupture through the periosteum (figure 1). The spread of infection is influenced by characteristics of the growing skeleton (figure 2) (see 'Pathogenesis' above):

• In the young infant, the thin cortex and loosely applied periosteum are poorly able to contain infection, which can extend into the surrounding soft tissue. The metaphyseal blood supply, which crosses the epiphyseal growth plate, permits spread of infection to the epiphysis and joint space. (See 'Birth to three months' above.)

• In older infants, children, and adolescents, the thicker cortex, denser periosteum, and atrophy of the metaphyseal capillaries prevent spread of infection to the soft tissues and epiphysis. However, joint infection may still occur if the metaphysis is intracapsular (eg, shoulder, hip, ankle, elbow) or with simultaneous hematogenous infection. Subperiosteal abscess typically occurs at the metaphysis. (See 'Older infants and toddlers' above and 'Older children and adolescents' above.)

● Most cases of acute hematogenous osteomyelitis are caused by a single organism. However, no pathogen is isolated in approximately one-half of cases. Polymicrobial infections usually are associated with contiguous spread, trauma, vascular insufficiency, or immobility of an extremity. (See 'Microbiology' above.)

● Staphylococcus aureus is the most common cause of osteomyelitis in children. Community- associated methicillin-resistant S. aureus is associated with more severe infection than methicillin- sensitive S. aureus. (See 'Staphylococcus' above.)

● Other important bacterial causes of hematogenous osteomyelitis in children include groups A and B Streptococcus, Streptococcus pneumoniae, and Kingella kingae (the dominant cause of osteoarticular infections in several countries) (table 1). (See 'Microbiology' above.)

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30. Vorhies JS, Lindsay EA, Tareen NG, et al. Severity Adjusted Risk of Long-term Adverse Sequelae https://www.uptodate.com/...rint?search=osteomyelitis&source=search_result&selectedTitle=6~150&usage_type=default&display_rank=6[19.03.2020 15:28:37] Hematogenous osteomyelitis in children: Epidemiology, pathogenesis, and microbiology - UpToDate

Among Children With Osteomyelitis. Pediatr Infect Dis J 2019; 38:26.

31. Martínez-Aguilar G, Avalos-Mishaan A, Hulten K, et al. Community-acquired, methicillin-resistant and methicillin-susceptible Staphylococcus aureus musculoskeletal infections in children. Pediatr Infect Dis J 2004; 23:701.

32. Gonzalez BE, Martinez-Aguilar G, Hulten KG, et al. Severe Staphylococcal sepsis in adolescents in the era of community-acquired methicillin-resistant Staphylococcus aureus. Pediatrics 2005; 115:642.

33. Bocchini CE, Hulten KG, Mason EO Jr, et al. Panton-Valentine leukocidin genes are associated with enhanced inflammatory response and local disease in acute hematogenous Staphylococcus aureus osteomyelitis in children. Pediatrics 2006; 117:433.

34. Gonzalez BE, Teruya J, Mahoney DH Jr, et al. Venous thrombosis associated with staphylococcal osteomyelitis in children. Pediatrics 2006; 117:1673.

35. McCaskill ML, Mason EO Jr, Kaplan SL, et al. Increase of the USA300 clone among community- acquired methicillin-susceptible Staphylococcus aureus causing invasive infections. Pediatr Infect Dis J 2007; 26:1122.

36. Ritz N, Curtis N. The role of Panton-Valentine leukocidin in Staphylococcus aureus musculoskeletal infections in children. Pediatr Infect Dis J 2012; 31:514.

37. Ibia EO, Imoisili M, Pikis A. Group A beta-hemolytic streptococcal osteomyelitis in children. Pediatrics 2003; 112:e22.

38. Olarte L, Romero J, Barson W, et al. Osteoarticular Infections Caused by Streptococcus pneumoniae in Children in the Post-Pneumococcal Conjugate Vaccine Era. Pediatr Infect Dis J 2017; 36:1201.

39. Yagupsky P, Porsch E, St Geme JW 3rd. Kingella kingae: an emerging pathogen in young children. Pediatrics 2011; 127:557.

40. Chometon S, Benito Y, Chaker M, et al. Specific real-time polymerase chain reaction places Kingella kingae as the most common cause of osteoarticular infections in young children. Pediatr Infect Dis J 2007; 26:377.

41. El Houmami N, Minodier P, Dubourg G, et al. Patterns of Kingella kingae Disease Outbreaks. Pediatr Infect Dis J 2016; 35:340.

42. Samara E, Spyropoulou V, Tabard-Fougère A, et al. Kingella kingae and Osteoarticular Infections. Pediatrics 2019; 144.

43. Ceroni D, Kampouroglou G, Valaikaite R, et al. Osteoarticular infections in young children: what has https://www.uptodate.com/...rint?search=osteomyelitis&source=search_result&selectedTitle=6~150&usage_type=default&display_rank=6[19.03.2020 15:28:37] Hematogenous osteomyelitis in children: Epidemiology, pathogenesis, and microbiology - UpToDate

changed over the last years? Swiss Med Wkly 2014; 144:w13971.

44. Juchler C, Spyropoulou V, Wagner N, et al. The Contemporary Bacteriologic Epidemiology of Osteoarticular Infections in Children in Switzerland. J Pediatr 2018; 194:190.

45. Verdier I, Gayet-Ageron A, Ploton C, et al. Contribution of a broad range polymerase chain reaction to the diagnosis of osteoarticular infections caused by Kingella kingae: description of twenty-four recent pediatric diagnoses. Pediatr Infect Dis J 2005; 24:692.

46. Kiang KM, Ogunmodede F, Juni BA, et al. Outbreak of osteomyelitis/septic arthritis caused by Kingella kingae among child care center attendees. Pediatrics 2005; 116:e206.

47. De Jonghe M, Glaesener G. [Type B Haemophilus influenzae infections. Experience at the Pediatric Hospital of Luxembourg]. Bull Soc Sci Med Grand Duche Luxemb 1995; 132:17.

48. Ratnayake K, Davis AJ, Brown L, Young TP. Pediatric acute osteomyelitis in the postvaccine, methicillin-resistant Staphylococcus aureus era. Am J Emerg Med 2015; 33:1420.

49. Sakellaris G, Kampitakis E, Karamitopoulou E, et al. Cat scratch disease simulating a malignant process of the chest wall with coexistent osteomyelitis. Scand J Infect Dis 2003; 35:433.

50. Mirakhur B, Shah SS, Ratner AJ, et al. Cat scratch disease presenting as orbital abscess and osteomyelitis. J Clin Microbiol 2003; 41:3991.

51. Hajjaji N, Hocqueloux L, Kerdraon R, Bret L. Bone infection in cat-scratch disease: a review of the literature. J Infect 2007; 54:417.

52. Erdem G, Watson JR, Hunt WG, et al. Clinical and Radiologic Manifestations of Bone Infection in Children with Cat Scratch Disease. J Pediatr 2018; 201:274.

53. Bartkowski SB, Zapala J, Heczko P, Szuta M. Actinomycotic osteomyelitis of the mandible: review of 15 cases. J Craniomaxillofac Surg 1998; 26:63.

54. Gregory SW, Boyce TG, Larson AN, et al. Fusobacterium nucleatum Osteomyelitis in 3 Previously Healthy Children: A Case Series and Review of the Literature. J Pediatric Infect Dis Soc 2015; 4:e155.

55. Brook I. Microbiology and management of joint and bone infections due to anaerobic bacteria. J Orthop Sci 2008; 13:160.

56. Galgiani JN, Ampel NM, Catanzaro A, et al. Practice guideline for the treatment of coccidioidomycosis. Infectious Diseases Society of America. Clin Infect Dis 2000; 30:658.

57. Sondermeyer GL, Lee LA, Gilliss D, et al. Epidemiology of Pediatric Coccidioidomycosis in California, 2000-2012. Pediatr Infect Dis J 2016; 35:166.

58. Ho AK, Shrader MW, Falk MN, Segal LS. Diagnosis and initial management of musculoskeletal coccidioidomycosis in children. J Pediatr Orthop 2014; 34:571.

59. Bisla RS, Taber TH Jr. Coccidioidomycosis of bone and joints. Clin Orthop Relat Res 1976; :196.

60. Corrall CJ, Merz WG, Rekedal K, Hughes WT. Aspergillus osteomyelitis in an immunocompetent adolescent: a case report and review of the literature. Pediatrics 1982; 70:455.

61. Winkelstein JA, Marino MC, Johnston RB Jr, et al. Chronic granulomatous disease. Report on a national registry of 368 patients. Medicine (Baltimore) 2000; 79:155.

62. Nelson JD. Acute osteomyelitis in children. Infect Dis Clin North Am 1990; 4:513.

63. Gill FM, Sleeper LA, Weiner SJ, et al. Clinical events in the first decade in a cohort of infants with sickle cell disease. Cooperative Study of Sickle Cell Disease. Blood 1995; 86:776.

64. Bennett OM. Salmonella osteomyelitis and the hand-foot syndrome in sickle cell disease. J Pediatr Orthop 1992; 12:534.

65. Webb DK, Serjeant GR. Haemophilus influenzae osteomyelitis complicating dactylitis in homozygous sickle cell disease. Eur J Pediatr 1990; 149:613.

66. Chambers JB, Forsythe DA, Bertrand SL, et al. Retrospective review of osteoarticular infections in a pediatric sickle cell age group. J Pediatr Orthop 2000; 20:682.

67. Burnett MW, Bass JW, Cook BA. Etiology of osteomyelitis complicating sickle cell disease. Pediatrics 1998; 101:296.

68. HOOK EW, CAMPBELL CG, WEENS HS, COOPER GR. Salmonella osteomyelitis in patients with sickle-cell anemia. N Engl J Med 1957; 257:403.

69. Syrogiannopoulos GA, McCracken GH Jr, Nelson JD. Osteoarticular infections in children with sickle cell disease. Pediatrics 1986; 78:1090.

70. Sadat-Ali M. The status of acute osteomyelitis in sickle cell disease. A 15-year review. Int Surg 1998; 83:84.

71. Robertson AJ, Firth GB, Truda C, et al. Epidemiology of acute osteoarticular sepsis in a setting with a high prevalence of pediatric HIV infection. J Pediatr Orthop 2012; 32:215.

Topic 6063 Version 25.0

GRAPHICS

Pathogenesis of acute osteomyelitis in children

(A) During an episode of bacteremia, bacteria are deposited in the metaphysis from the metaphyseal vessels (nutrient artery and vein). (B) A focus of infection develops in the metaphysis, which leads to cellulitis in the bone marrow. (C) Exudate under pressure is forced laterally through the Haversian systems and Volkmann canals and into the cortex of the bone, where it can lift or rupture through the periosteum.

Graphic 65719 Version 4.0

Brodie abscess radiograph

Lateral (A) and frontal (B) radiographs of the right lower extremity demonstrate an ovoid lucent lesion in the medullary cavity of the proximal metadiaphysis of the tibia (arrows) with associated periosteal reaction (arrowheads). The lateral radiograph (A) also demonstrates irregular cortical lucency anteriorly suggesting an area of focal cortical disruption (dashed arrow).

Graphic 87102 Version 5.0

Developmental pathogenesis of acute osteomyelitis

(A) In newborns, infection commonly spreads along the subperiosteal space and ruptures through the cortex into soft tissue or adjacent joint spaces. (B and C) In infants and older children, capillaries do not cross the physis. Infection in older children is generally confined to the metaphysis, and the thicker cortex and denser periosteum limit spread to soft tissues.

Graphic 50672 Version 5.0

Clinical features associated with bacterial pathogens that cause acute hematogenous osteomyelitis in children

Clinical features

Gram-positive bacteria

Staphylococcus aureus All ages; possible associated skin or soft tissue infection; MRSA may be associated with venous thromboembolism and pulmonary disease

Coagulase-negative Neonates in intensive care unit; children with indwelling vascular catheters (eg, for staphylococci chronic hemodialysis)

Group A Streptococcus More common in children younger than 4 years; may occur as a complication of concurrent varicella-zoster virus infection

Group B Streptococcus Infants younger than 3 months (usually 2 to 4 weeks)

Streptococcus pneumoniae Children younger than 2 years who are incompletely immunized; children older than 2 years with underlying medical conditions (eg, sickle cell disease, asplenia, splenic dysfunction, immunodeficiency, chronic heart disease, chronic lung disease, diabetes mellitus)

Actinomyces May affect the facial bones, the pelvis, or vertebral bodies

Gram-negative bacteria

Kingella kingae Children 6 to 36 months; indolent onset; oral ulcers preceding musculoskeletal findings; may affect nontubular bones

Nonsalmonella gram-negative Birth to 3 months; children with sickle cell disease; instrumentation of the bacilli (eg, Escherichia coli, gastrointestinal or urinary tract; immunocompromised host (eg, CGD) Serratia)

Haemophilus influenzae type b Incompletely immunized children in areas with low Hib immunization rates

Bartonella henselae Children with cat exposure; may affect the vertebral column and pelvic girdle; may cause multifocal infection

Pseudomonas aeruginosa Injectable drug use

Brucella Travel to or living in an endemic area; ingestion of unpasteurized dairy products

Mycobacterium tuberculosis Birth in, travel to, or contact with a visitor from, a region endemic for M. tuberculosis

Nontuberculous mycobacteria Surgery or penetrating injury; CGD; other underlying immunodeficiency; HIV infection

Salmonella species Children with sickle cell disease or related hemoglobinopathies; exposure to reptiles or amphibians; children with gastrointestinal symptoms; children in developing countries

Polymicrobial infection More likely with direct inoculation (eg, penetrating trauma) or contiguous spread (eg, from skull, face, hands, feet)

MRSA: methicillin-resistant S. aureus; CGD: chronic granulomatous disease; Hib: H. influenzae type b.

Graphic 96510 Version 8.0

Contributor Disclosures

Paul Krogstad, MD Nothing to disclose Sheldon L Kaplan, MD Grant/Research/Clinical Trial Support: Pfizer [Streptococcus pneumoniae]; Merck [Staphylococcus aureus]; MeMed Diagnostics [Bacterial and viral infections]. Consultant/Advisory Board: Pfizer [Staphylococcus aureus]. Other Financial Interest: Pfizer [Speaker on PCV13, linezolid]; Medscape [Video discussion on bacterial meningitis]; Elsevier [Co-editor (Feigin and Cherry Textbook of Pediatric Infectious Diseases)]. William A Phillips, MD Nothing to disclose Mary M Torchia, MD Nothing to disclose

Contributor Disclosures

Conflict of interest policy

Author: Paul Krogstad, MD Section Editors: Sheldon L Kaplan, MD, William A Phillips, MD Deputy Editor: Mary M Torchia, MD

All topics are updated as new evidence becomes available and our peer review process is complete.

Literature review current through: Feb 2020. | This topic last updated: Feb 22, 2019.

INTRODUCTION

The evaluation and diagnosis of hematogenous osteomyelitis in children will be discussed here. The epidemiology, pathogenesis, microbiology, clinical features, complications, and management of osteomyelitis in children osteomyelitis are discussed separately:

● (See "Hematogenous osteomyelitis in children: Epidemiology, pathogenesis, and microbiology".) ● (See "Hematogenous osteomyelitis in children: Clinical features and complications".) ● (See "Hematogenous osteomyelitis in children: Management".)

DEFINITION AND PATHOGENESIS

Osteomyelitis is an infection localized to bone. It is usually caused by microorganisms (predominantly bacteria) that enter the bone hematogenously.

Osteomyelitis also may result from direct inoculation of bone with bacteria in association with an open fracture or as a complication of puncture wounds or the placement of orthopedic hardware (such as pins or screws). (See "Infectious complications of puncture wounds".)

Less commonly, osteomyelitis may arise as an extension of a contiguous infection (eg, decubitus ulcer, sinusitis, periodontal disease).

DIAGNOSTIC APPROACH

Overview — The diagnosis of osteomyelitis is supported by a combination of [1]:

● Clinical features suggestive of bone infection (constitutional symptoms, focal symptoms and signs of https://www.uptodate.com/...rint?search=osteomyelitis&source=search_result&selectedTitle=5~150&usage_type=default&display_rank=5[19.03.2020 15:29:00] Hematogenous osteomyelitis in children: Evaluation and diagnosis - UpToDate

bone inflammation, limitation of function, elevated erythrocyte sedimentation rate [ESR], and/or C- reactive protein [CRP]) (see 'Clinical suspicion' below and 'Blood tests' below)

● An imaging study with abnormalities characteristic of osteomyelitis (table 1) (see 'Plain radiographs' below and 'Advanced imaging' below)

● A positive microbiologic or histopathologic specimen (see 'Microbiology' below and 'Histopathology' below)

● A response to empiric antimicrobial therapy (see 'Response to empiric therapy' below)

The diagnosis often is unclear at the initial evaluation. The initial presentation may be delayed, and signs and symptoms nonspecific. A high index of suspicion and monitoring of the clinical course are essential to establishing the diagnosis. We suggest that an orthopedic surgeon or interventional radiologist be consulted as early as possible to assist in obtaining specimens from the site of infection and assessing the need for surgical intervention. (See 'Microbiology' below and "Hematogenous osteomyelitis in children: Management", section on 'Indications for surgery'.)

The diagnosis is confirmed by histopathologic evidence of inflammation in a surgical specimen of bone (picture 1A-C) (if obtained) or identification of a pathogen by culture or Gram stain in an aspirate or biopsy of bone [2].

The diagnosis is probable in a child with compatible clinical, laboratory, and/or radiologic findings (table 1) in whom a pathogen is isolated from blood, periosteal collection, or joint fluid. We also consider the diagnosis to be probable in a child with compatible clinical, laboratory, and radiologic findings and negative cultures if he or she responds as expected to empiric antimicrobial therapy.

The diagnosis is unlikely if advanced imaging studies (particularly magnetic resonance imaging [MRI]) are normal.

Clinical suspicion — Based upon the history and physical examination, acute hematogenous osteomyelitis should be suspected in infants and children with findings suggestive of bone infection, including:

● Constitutional symptoms (irritability, decreased appetite or activity), with or without fever

● Focal symptoms and signs of bone inflammation (eg, warmth, swelling, point tenderness) that typically progress over several days to a week; symptoms and signs in infants and small children may be poorly localized

● Limitation of function (limited use of an extremity; limp; refusal to walk, crawl, sit, or bear weight)

Additional clinical features of osteomyelitis in children are discussed separately. (See "Hematogenous osteomyelitis in children: Clinical features and complications", section on 'Clinical features'.)

Osteomyelitis also should also be considered in children who are found to have bacteremia or an https://www.uptodate.com/...rint?search=osteomyelitis&source=search_result&selectedTitle=5~150&usage_type=default&display_rank=5[19.03.2020 15:29:00] Hematogenous osteomyelitis in children: Evaluation and diagnosis - UpToDate

abnormal imaging study of bone in the evaluation of trauma or nonspecific signs or symptoms (eg, irritability, fever without a source).

Risk factors that may raise suspicion for osteomyelitis include (see "Hematogenous osteomyelitis in children: Epidemiology, pathogenesis, and microbiology", section on 'Risk factors'):

● Bacteremia or sepsis ● Immune deficiency (eg, sickle cell disease, chronic granulomatous disease) ● Indwelling vascular catheter, including hemodialysis catheter ● For neonates – Prematurity, skin infection, complicated delivery, urinary tract anomalies, late onset neonatal sepsis

Initial evaluation — The initial evaluation for children with suspected osteomyelitis includes blood tests and plain radiographs of the affected area(s).

Blood tests — Initial blood tests for children with suspected osteomyelitis include a complete blood count (CBC) with differential, ESR, and/or CRP [3]. To avoid multiple venipunctures, at least one blood culture should be obtained at the same time as these studies. Blood cultures are discussed below. (See 'Microbiology' below.)

At the time of presentation, elevation of ESR (>20 mm/h) and/or CRP (>10 to 20 mg/L [1 to 2 mg/dL]) is sensitive (approximately 95 percent) in cases of culture-proven osteomyelitis in children, but ESR and CRP are nonspecific [4-6]. Elevated ESR and/or CRP support the diagnosis of osteomyelitis but do not exclude other conditions in the differential diagnosis. ESR and CRP may be normal early in the infection in some patients, and repeat testing may be warranted within 24 hours in children in whom osteomyelitis is strongly suspected. ESR and CRP also are important markers for evaluating the response to therapy. (See "Hematogenous osteomyelitis in children: Management", section on 'Response to therapy'.)

Elevation of the white blood cell (WBC) count is variable and nonspecific [7]. In a 2012 systematic review of >12,000 patients, the WBC was elevated in only 36 percent [5]. However, the CBC and differential are helpful in evaluating other considerations in the differential diagnosis of children with bone pain (eg, vaso- occlusive crisis in sickle cell disease, leukemia). (See 'Differential diagnosis' below.)

Plain radiographs — Plain radiograph(s) of the affected region(s) should be performed as the initial imaging study to exclude other causes of pain (eg, bone tumors and fractures) [3,8,9]. Plain radiographs are usually normal or inconclusive early in the course of osteomyelitis, often necessitating advanced imaging when osteomyelitis is suspected. Newborn infants are an exception to this general rule; plain radiographs are abnormal at the time of evaluation in most newborn and young infants who are ultimately found to have osteomyelitis [10,11]. (See 'Advanced imaging' below and 'Differential diagnosis' below.)

Characteristic findings — Children with suspected osteomyelitis and characteristic abnormalities on initial plain radiographs are likely to have osteomyelitis (table 1). They should receive empiric antibiotic therapy pending further evaluation (microbiology and possibly additional imaging studies). (See

https://www.uptodate.com/...rint?search=osteomyelitis&source=search_result&selectedTitle=5~150&usage_type=default&display_rank=5[19.03.2020 15:29:00] Hematogenous osteomyelitis in children: Evaluation and diagnosis - UpToDate

"Hematogenous osteomyelitis in children: Management", section on 'Empiric parenteral therapy' and 'Microbiology' below and 'Advanced imaging' below.)

Plain radiographic findings that are compatible with osteomyelitis include:

● Evidence of periosteal new bone formation (periosteal reaction) (image 1A-B) ● Periosteal elevation (suggestive of periosteal abscess) (image 1D) ● Lytic lesions (image 1C) or sclerosis, indicating subacute/chronic infection

However, these findings generally are not apparent at the onset of symptoms. The timing and typical sequence of radiographic changes of osteomyelitis varies depending on which bones are affected and the age of the patient.

● Long bones – The typical sequence of radiographic changes in long bones of children is as follows [12,13]:

• Approximately three days after symptom onset – Small area of localized, deep, soft-tissue swelling in the region of the metaphysis (image 2)

• Three to seven days after symptom onset – Obliteration of the translucent fat planes interposed within muscle by edema fluid

• Ten to 21 days after symptom onset (7 to 10 days in neonates) – Evidence of bone destruction (osteopenia, osteolytic lesions), periosteal reaction, cortical thickening, periosteal elevation (due to subcortical purulence (image 1A-D)); these lesions may require surgical debridement or drainage (see "Hematogenous osteomyelitis in children: Management", section on 'Indications for surgery')

• One month or longer – Lytic sclerosis

● Membranous, irregular bones – Bone destruction and periosteal elevation generally are apparent two to three weeks later than in long bones.

● Pelvic bones – Plain radiographs usually are not useful in the diagnostic evaluation of osteomyelitis of the pelvis; they were abnormal in only 25 percent of patients in one large series [14].

● Vertebral osteomyelitis – In children with vertebral osteomyelitis, plain films may be normal at initial presentation in more than 50 percent of cases [15]. Initial abnormalities may include localized rarefaction of one vertebral plateau, followed by involvement of adjacent vertebrae. Marked destruction of bone, usually anteriorly, can occur, followed by anterior osteophytic reactions with bridging and bone sclerosis.

● Discitis – The radiographic changes of discitis are first noted several weeks after the onset of symptoms, with the following sequence:

• Narrowing of the disc space two to four weeks after the onset of symptoms

• Destruction of the adjacent cartilaginous vertebral end-plates

• Herniation of the disc into the vertebral body

In older children, anterior spontaneous fusion is common. Rarely, vertebral body compression or wedging is noted.

Despite the delay in radiographic changes, findings suggestive of discitis often are apparent at the time of presentation (because of the indolent course). In one series, as an example, radiographic changes were present on initial evaluation in more than 70 percent of cases [15].

Normal plain radiographs — A normal plain radiograph early in the course (eg, within seven days of symptom onset) does not exclude osteomyelitis. Children with suspected osteomyelitis (eg, localized bone pain, limited function, elevated ESR or CRP) and normal initial plain radiographs generally should receive empiric antibiotic therapy pending additional imaging and the results of microbiologic studies. However, school-age children who are afebrile and have equivocal physical examination findings, and normal plain radiographs may occasionally be followed closely without antimicrobial therapy pending additional evaluation. (See "Hematogenous osteomyelitis in children: Management", section on 'Empiric parenteral therapy' and 'Advanced imaging' below and 'Microbiology' below.)

Further imaging, usually with MRI or scintigraphy, should be performed as soon as possible in any child with suspected osteomyelitis whose initial radiographs are normal, regardless of whether antibiotic therapy is initiated (image 3). (See 'Advanced imaging' below.)

Advanced imaging — Most children with suspected osteomyelitis undergo additional imaging with MRI, scintigraphy, computed tomography (CT), and/or ultrasonography (table 2). Indications for additional imaging studies may include:

● Confirmation of the diagnosis in children with normal initial plain radiographs ● Further evaluation of abnormalities identified on plain radiographs (eg, bone destruction) ● Evaluation of extension of infection (eg, growth plate, epiphysis, joint, adjacent soft tissues) ● Guidance for percutaneous diagnostic and therapeutic drainage procedures (eg, needle aspiration, abscess drainage)

Magnetic resonance imaging — If it is available, MRI is the imaging modality of choice when imaging other than plain radiography is needed to establish the diagnosis of osteomyelitis (eg, early in the course) or to delineate the location and extent of bone and soft tissue involvement (table 2) [3,8,9]. Intravenous contrast is not generally required but may help define intramedullary abscess or intramuscular abscesses [16]. Osteomyelitis is unlikely if MRI is negative.

MRI is particularly useful in identifying and/or distinguishing:

● Early changes in the bone marrow cavity (before changes in cortical bone are apparent on plain radiographs) [17]

● Pelvic osteomyelitis [18-20]

● Involvement of the vertebral body and the adjacent disc in children with vertebral osteomyelitis

● Areas that may require surgical drainage (eg, sinus tracts, intraosseous abscesses, subperiosteal or soft-tissue collections of pus) (image 4) (see "Hematogenous osteomyelitis in children: Management", section on 'Indications for surgery')

● Involvement of the growth plate (image 3) [21-23]

● Contiguous septic arthritis (especially in the evaluation of young children with possible septic arthritis of the hip or femoral osteomyelitis)

● Associated pyomyositis

● Evidence of venous thrombosis

The major advantages of MRI compared with other imaging modalities include accurate identification of subperiosteal or soft-tissue collections of pus and avoidance of exposure to ionizing radiation [24]. In addition, the efficacy of MRI does not appear to be affected by diagnostic or surgical intervention.

Disadvantages of MRI include a longer scanning time than CT and the need for sedation or general anesthesia for an adequate study in most young children, which may be a limiting factor in some institutions. MRI is less useful when multiple sites of involvement are suspected or there are no localized clinical findings. Finally, MRI is not always readily available.

MRI demonstrates excellent anatomic detail and differentiation among soft tissue, bone marrow, and bone (image 5).

● Areas of active inflammation show a decreased signal in T1-weighted images and an increased signal in T2-weighted images [25]. Fat-suppression sequences, including short-tau inversion recovery (STIR), decrease the signal from fat and are more sensitive for the detection of bone- marrow edema.

● The penumbra sign (high-intensity-signal transition zone between abscess and sclerotic bone marrow in T1-weighted images (image 6)) is characteristic of subacute osteomyelitis and in one study was helpful in differentiating between indolent infections and neoplasms [26].

● The signal from infected bone marrow can be enhanced with intravenous gadolinium contrast [27], but this is seldom necessary for diagnostic purposes [16,28]. Because of the risk of nephrogenic systemic fibrosis, imaging with gadolinium should be avoided, if possible, in patients with moderate or advanced renal failure. (See "Nephrogenic systemic fibrosis/nephrogenic fibrosing dermopathy in advanced kidney disease".)

MRI abnormalities in discitis include reduction of disc space, increased T2 signal in the adjacent vertebral

end plates, and signal intensity changes in the intervening discs [15,17].

The sensitivity and specificity for the detection of bone involvement in children with suspected osteomyelitis with MRI are high (80 to 100 percent and 70 to 100 percent, respectively, in a 2012 systematic review) [5]. Given the high sensitivity, osteomyelitis is unlikely if the MRI is negative [8]. False- positive results may occur in patients with adjacent soft tissue infection; adjacent soft tissue infection can cause edema of the bone that may be interpreted as "consistent with osteomyelitis" but represents sympathetic inflammation rather than bone infection.

Scintigraphy — We suggest scintigraphy (also known as radionuclide scanning or bone scan) when MRI is not available and imaging other than plain radiography is needed to establish the diagnosis of osteomyelitis (table 2). Scintigraphy also may be useful when the area of suspected infection cannot be localized or multiple areas of involvement are suspected.

Scintigraphy is helpful early in the course, readily available, relatively inexpensive, and requires sedation less frequently than MRI in young children. However, it does not provide information about the extent of purulent collections that may require drainage (eg, intramedullary abscess, muscular phlegmon) [8]. Scintigraphy may be falsely negative if the blood supply to the periosteum is disrupted (eg, subperiosteal abscess) and during the transition between decreased and increased activity [29,30]. In addition, scintigraphy involves exposure to ionizing radiation [31].

The three-phase bone scan utilizing technetium 99m (99mTc) usually is performed as the initial nuclear medicine procedure in the evaluation of osteomyelitis. It consists of:

● A nuclear angiogram (the flow phase), obtained two to five seconds after injection ● The blood pool phase, obtained 5 to 10 minutes after injection ● The delayed phase, specific for bone uptake, obtained two to four hours after injection

Increased uptake of tracer in the first two phases can be caused by anything that increases blood flow and is accompanied by inflammation. Osteomyelitis causes focal uptake in the third phase; the intensity of the signal reflects the level of osteoblastic activity. Localization of a lesion near a growth plate can complicate interpretation.

The sensitivity and specificity for the detection of bone involvement in children with suspected osteomyelitis with scintigraphy generally are high, but the range is wider than MRI (53 to 100 percent and 50 to 100 percent, respectively in a 2012 systematic review) [5]. Sensitivity is variable in neonates but appears to be lower than in older children [10,32,33]. Scintigraphy has been shown to have poor sensitivity (53 percent) in cases of osteomyelitis caused by methicillin-resistant Staphylococcus aureus (MRSA) [8].

MRI generally is preferred if the results of the three-phase 99mTc bone scan are equivocal. Scintigraphy with inflammation imaging tracers (eg, gallium or indium) may be helpful but involve additional exposure to radiation.

Computed tomography — MRI usually is preferred to CT in the evaluation of suspected osteomyelitis. However, CT better delineates changes in bone and may be preferred when significant bone destruction is identified on plain radiographs [17]. CT findings of osteomyelitis include increased density of bone marrow, periosteal new bone formation, and periosteal purulence.

Other potential indications for CT may include:

● Delineation of the extent of bone injury in chronic osteomyelitis or planning the surgical approach to debridement of devitalized bone (sequestra)

● Lack of availability of MRI or contraindications to MRI

CT is less time consuming than MRI, and young children usually do not require sedation. However, CT exposes children to ionizing radiation.

Ultrasonography — Ultrasonography usually is not helpful in the diagnosis of osteomyelitis. However, it can identify fluid collections associated with bone infections and may improve the success of percutaneous diagnostic and therapeutic drainage procedures [9,34].

Ultrasonography findings consistent with osteomyelitis include fluid collection adjacent to the bone without intervening soft tissue, elevation of the periosteum by more than 2 mm, and thickening of the periosteum. (See "Approach to imaging modalities in the setting of suspected nonvertebral osteomyelitis", section on 'Ultrasonography'.)

Microbiology

General principles — Isolation of a pathogen from bone, subperiosteal fluid collection, joint fluid, or blood establishes a diagnosis of confirmed or probable osteomyelitis in children with compatible clinical and/or radiologic findings and speciation and susceptibility testing are essential for planning treatment. (See "Hematogenous osteomyelitis in children: Management", section on 'Antimicrobial therapy'.)

With an increasing proportion of cases caused by antibiotic-resistant organisms (eg, community- associated MRSA) and previously unusual species (eg, Kingella kingae in young children), it is particularly important to collect specimens for culture from as many sites of infection as possible.

It is preferable to obtain microbiologic specimens before administration of antibiotics, but this must be weighed against the potential for additional complications of ongoing bacteremia by S. aureus or other pathogens. If bone culture cannot be obtained immediately, decisions regarding immediate or delayed administration of antibiotics generally are made in consultation with the orthopedic surgeon. For children with signs of systemic illness (eg, fever, tachycardia), we provide antibiotic therapy immediately following blood culture. In a retrospective review of 250 cases of osteomyelitis, the rates of culture positivity were similar (approximately 74 percent) whether or not patients received antibiotics before cultures were obtained, although there was a tendency for cultures obtained by interventional radiology to more likely be positive if obtained within 24 hours of initiating antibiotic treatment [35]. In another retrospective study,

operative cultures were positive in 42 of 50 children (84 percent) with osteomyelitis who received preoperative antibiotics [36].

Sites to culture — Specimens for culture should be obtained from blood and as many potential sites of infection as possible. An orthopedic surgeon and/or interventional radiologist should be consulted as early as possible in the evaluation of children with suspected osteomyelitis to assist in obtaining specimens for histopathology and/or culture and assessing the need for surgical intervention. In a retrospective review of 250 cases of osteomyelitis from a single institution, blood cultures were positive in 46 percent of cases in which they were obtained, cultures obtained in the operating room (OR, bone, subperiosteal abscess, adjacent septic arthritis) were positive in 82 percent, and cultures obtained in interventional radiology (IR) were positive in 52 percent [35]. OR/IR cultures were positive in 80 patients who had negative blood cultures; among these cases, results of OR/IR cultures prompted a change in antibiotic therapy in 68 (85 percent).

It is important to let the microbiology lab know if less common or fastidious organisms (eg, K. kingae) are suspected because they may require specific media, growth conditions, or prolonged culture time (table 3) [37].

● Blood cultures – We recommend at least one, and preferably two, blood cultures be obtained before administration of antibiotics to children with osteomyelitis. Although less frequently positive than cultures from bone or adjacent abscesses, blood cultures may be the only positive source of identification of the pathogen [5,35,37,38].

● Bone culture – Bone samples for culture, Gram stain, and histopathology should be obtained whenever possible [35,38]. Culture specimens may be obtained by percutaneous needle aspiration (which may be guided by ultrasonography, fluoroscopy, or other imaging modality) or open biopsy (particularly if surgery is required for therapeutic drainage and debridement). (See "Hematogenous osteomyelitis in children: Management", section on 'Indications for surgery'.)

● Other cultures – Subperiosteal exudate, joint fluid, and pus from adjoining sites of infection should be obtained and sent for Gram stain and culture whenever possible, as directed by imaging studies [35]. Specimens may be obtained by percutaneous needle aspiration (which may be guided by ultrasonography, fluoroscopy, or other imaging modality). Injection of bone aspirates or periosteal collections into blood culture bottles is recommended to enhance recovery of K. kingae [39,40]. (See "Hematogenous osteomyelitis in children: Epidemiology, pathogenesis, and microbiology", section on 'Kingella kingae'.)

Percutaneous needle aspiration is often successful in neonates with extensive soft-tissue and periosteal involvement and infants and young children with subperiosteal collections.

Percutaneous techniques are less successful in older children and adolescents, who may require bone aspiration or drilling to obtain culture specimens. In such cases, the risk of epiphyseal damage and further destruction of bone must be weighed against the benefit of obtaining a specimen.

As reported in a 2012 systematic review of observational studies of osteomyelitis (during or after 2000), a pathogen is isolated from any culture (blood, tissue, pus) in approximately 50 percent of cases [5]. The yield of cultures of bone tissue or pus is greater than that from blood cultures (70 versus 40 percent).

Other microbiologic studies — Other microbiologic studies may be helpful in the detection of specific pathogens. Polymerase chain reaction (if available) can be particularly helpful for detecting K. kingae in purulent materials or bone specimens [41-43].

Histopathology — The diagnosis of osteomyelitis is confirmed in children who have histopathologic evidence of inflammation in a surgical specimen of bone (picture 1A-C). An orthopedic surgeon and/or interventional radiologist should be consulted as early as possible in the evaluation of children with suspected osteomyelitis to assist in obtaining specimens for histopathology and/or culture and assessing the need for surgical intervention.

Histopathologic specimens may be obtained by percutaneous needle aspiration (which may be guided by ultrasonography, fluoroscopy, or other imaging modality) or open biopsy (particularly if surgery is required for therapeutic drainage and debridement). (See "Hematogenous osteomyelitis in children: Management", section on 'Indications for surgery'.)

Response to empiric therapy — Improvement in constitutional symptoms and localized inflammation (eg, erythema, point tenderness) with empiric antimicrobial therapy helps to support the diagnosis of osteomyelitis, particularly in children in whom no pathogen is isolated. (See "Hematogenous osteomyelitis in children: Management", section on 'Response to therapy' and 'Probable osteomyelitis' below.)

In children with normal MRI and/or scintigraphy, a lack of clinical response to empiric therapy and the results of blood cultures help to direct additional evaluation for other conditions in the differential diagnosis. (See 'Osteomyelitis unlikely (advanced imaging studies normal)' below and 'Differential diagnosis' below.)

DIAGNOSTIC INTERPRETATION

Confirmed osteomyelitis — The diagnosis of osteomyelitis is confirmed by histopathologic evidence of inflammation in a surgical specimen of bone (picture 1A-C) (if obtained) or identification of a pathogen by culture or Gram stain in an aspirate of bone [2].

Probable osteomyelitis — The diagnosis of osteomyelitis is probable in a child with compatible clinical, laboratory, and/or radiologic findings (table 2) in whom a pathogen is isolated from blood, periosteal collection, or joint fluid. We also consider the diagnosis to be probable in a child with compatible clinical, laboratory, and radiologic findings and negative cultures if he or she responds as expected to empiric antimicrobial therapy.

Given the potential morbidity of delayed treatment, children with probable osteomyelitis should be managed in the same manner as children in whom infection has been confirmed by isolation of an organism from bone or blood [44]. (See "Hematogenous osteomyelitis in children: Clinical features and complications", section on 'Complications' and "Hematogenous osteomyelitis in children: Management", section on 'Empiric parenteral therapy'.)

The response to empiric antimicrobial therapy in children with culture-negative osteomyelitis directs the need for additional evaluation. (See "Hematogenous osteomyelitis in children: Management", section on 'Culture-negative osteomyelitis'.)

Osteomyelitis unlikely (advanced imaging studies normal) — Osteomyelitis is unlikely if advanced imaging studies (usually magnetic resonance imaging or scintigraphy) are normal. The major considerations in the differential diagnosis and approach to continued evaluation and management depend upon the results of the blood culture and response to antimicrobial therapy:

● Positive blood culture, improvement with empiric therapy – A source of infection other than osteomyelitis must be sought (see 'Other infections' below)

● Positive blood culture, no improvement with appropriate therapy – Other sources of bacteremia and noninfectious conditions that may have predisposed the patient to bacteremia must be sought aggressively (see 'Differential diagnosis' below)

● Negative blood culture, improvement with empiric therapy – The child may have a more superficial source of infection (eg, cellulitis); a shorter course of antimicrobial therapy may be warranted (see 'Other infections' below)

● Negative blood culture, no improvement with appropriate therapy – A bacterial infection is unlikely; fungal and noninfectious causes of musculoskeletal pain should be sought; discontinuation of empiric antimicrobial therapy may be warranted (see 'Noninfectious conditions' below)

DIFFERENTIAL DIAGNOSIS

The differential diagnosis of osteomyelitis includes infectious conditions, noninfectious conditions, and radiographic mimics (table 4).

Other infections — Infections that do not involve bone may cause fever, pain, and tenderness overlying bone, mimicking hematogenous osteomyelitis. These infections usually are distinguished from osteomyelitis by imaging studies that lack the characteristic features of osteomyelitis (table 1). (See 'Advanced imaging' above.)

Other infections that may share features of osteomyelitis (and may complicate or be complicated by osteomyelitis) include:

● Septicemia (see "Clinical features, evaluation, and diagnosis of sepsis in term and late preterm https://www.uptodate.com/...rint?search=osteomyelitis&source=search_result&selectedTitle=5~150&usage_type=default&display_rank=5[19.03.2020 15:29:00] Hematogenous osteomyelitis in children: Evaluation and diagnosis - UpToDate

infants", section on 'Clinical manifestations' and "Systemic inflammatory response syndrome (SIRS) and sepsis in children: Definitions, epidemiology, clinical manifestations, and diagnosis", section on 'Clinical manifestations')

● Cellulitis (see "Cellulitis and skin abscess: Clinical manifestations and diagnosis", section on 'Cellulitis and erysipelas')

● Septic arthritis; approximately one-third of cases of osteomyelitis extend to the contiguous joint (as many as 75 percent in neonates) [45-48] (see "Bacterial arthritis: Clinical features and diagnosis in infants and children", section on 'Clinical features')

● Deep abscesses (eg, psoas abscess) (see "Psoas abscess", section on 'Clinical manifestations')

● Pyomyositis (see "Pyomyositis", section on 'Clinical manifestations')

Noninfectious conditions

Chronic nonbacterial osteomyelitis — Chronic nonbacterial osteomyelitis (CNO; also called chronic recurrent multifocal osteomyelitis [CRMO]) is a chronic inflammatory bone disorder that primarily affects children. It is characterized by bone pain with insidious onset. The initial presentation is similar to that of osteomyelitis. Imaging may localize the areas of bony involvement and indicate the absence of features suggestive of chronic osteomyelitis, such as an abscess or sinus tract. However, microbiologic and pathologic studies from bone biopsy specimens are generally necessary to differentiate CNO from osteomyelitis. The evaluation and treatment of CNO are discussed in detail separately. (See "Chronic nonbacterial osteomyelitis (CNO)/chronic recurrent multifocal osteomyelitis (CRMO)".)

Other noninfectious conditions — Several noninfectious conditions have clinical features that overlap with osteomyelitis. These include:

● Malignancy – Tumor growth can cause bone pain, and some children with malignancies (particularly leukemia and Ewing sarcoma) have fever as part of their initial presentation. Unlike those with osteomyelitis, symptoms can be intermittent in children with cancer. Affected children also fail to respond to empiric antibiotic therapy. Osteomyelitis and cancer involving bone are usually differentiated with bone biopsy. (See "Clinical assessment of the child with suspected cancer", section on 'Bone and joint pain' and "Overview of the clinical presentation and diagnosis of acute lymphoblastic leukemia/lymphoma in children" and "Clinical presentation, staging, and prognostic factors of the Ewing sarcoma family of tumors", section on 'Signs and symptoms' and "Bone tumors: Diagnosis and biopsy techniques".)

● Bone infarction – Bone infarction secondary to hemoglobinopathy, especially in infants with dactylitis, can be particularly difficult to distinguish from osteomyelitis.

Plain radiographs, scintigraphy, and MRI all show similar results in both conditions. Unlike bone disease with hemoglobinopathy, osteomyelitis does not respond to hydration and other supportive

measures. (See "Acute and chronic bone complications of sickle cell disease".)

● Vitamin C deficiency – Vitamin C deficiency (scurvy) may cause musculoskeletal pain and refusal to bear weight, particularly in children with autism spectrum disorder, intellectual disability, food aversion, or limited food preferences [49]. Additional findings of vitamin C deficiency may include petechiae, ecchymoses, bleeding gums, coiled hairs, and hyperkeratosis (picture 2). (See "Overview of water-soluble vitamins", section on 'Deficiency'.)

● Gaucher disease – Children with Gaucher disease can have painful bone crises similar to those that occur in patients with sickle cell disease. During bone pain crises, ischemia can be detected by technetium bone scan. Radiographs of the distal femur may demonstrate deformities caused by abnormal modeling of the metaphysis that are characteristic of Gaucher disease. However, the possibility of osteomyelitis should be considered in febrile patients with Gaucher disease who do not improve with hydration and other supportive measures. (See "Gaucher disease: Pathogenesis, clinical manifestations, and diagnosis" and "Gaucher disease: Treatment", section on 'Skeletal disease'.)

● Complex regional pain syndrome – Complex regional pain syndrome (CRPS) is an uncommon chronic condition that causes pain, swelling, and limited range of motion in the affected extremity. It frequently begins after an injury, surgery, or vascular event. Vasomotor instability and chronic skin changes also occur. CRPS may be distinguished from osteomyelitis by autonomic dysfunction and normal ESR/CRP. (See "Complex regional pain syndrome in children", section on 'Diagnosis'.)

● Caffey disease – Caffey disease (infantile cortical hyperostosis) is an inherited disease characterized by fever, subperiosteal bone hyperplasia, and swelling of overlying soft tissues. It is a rare disorder and is difficult to distinguish from osteomyelitis on initial presentation. The disorders can be distinguished on bone biopsy. (See "Differential diagnosis of the orthopedic manifestations of child abuse", section on 'Infantile cortical hyperostosis (Caffey disease)'.)

Radiographic mimics — Benign and malignant bone tumors and tumors involving bone can have radiographic appearance similar to osteomyelitis. The acute clinical features and response to antibiotics in children with osteomyelitis usually distinguish osteomyelitis from these conditions. However, bone biopsy can be performed if necessary for histopathologic differentiation.

Bone lesions that can have radiographic appearance similar to osteomyelitis include (table 4):

● Fibrous dysplasia (see "Nonmalignant bone lesions in children and adolescents", section on 'Fibrous dysplasia')

● Osteoid osteoma and osteoblastoma (see "Nonmalignant bone lesions in children and adolescents", section on 'Bone-forming lesions')

● Chondroblastoma and chondromyxoid fibroma (see "Nonmalignant bone lesions in children and adolescents", section on 'Cartilage-forming tumors')

● Eosinophilic granuloma and other forms of histiocytosis (see "Langerhans cell histiocytosis (eosinophilic granuloma) of bone in children and adolescents")

● Osteosarcoma (see "Osteosarcoma: Epidemiology, pathogenesis, clinical presentation, diagnosis, and histology", section on 'Clinical presentation')

SOCIETY GUIDELINE LINKS

SUMMARY AND RECOMMENDATIONS

● The diagnosis of osteomyelitis is supported by a combination of clinical features suggestive of bone infection, an imaging study with abnormalities characteristic of osteomyelitis (table 1), a positive microbiologic or histopathologic specimen, and/or a response to empiric antimicrobial therapy.

The diagnosis often is unclear at the initial evaluation. A high index of suspicion and monitoring of the clinical course are essential to establishing the diagnosis. An orthopedic surgeon and/or interventional radiologist should be consulted as early as possible in the evaluation to assist in obtaining specimens for culture and/or histopathology. (See 'Overview' above.)

● Acute hematogenous osteomyelitis should be suspected in infants and children with findings suggestive of bone infection, including:

• Constitutional symptoms (irritability, decreased appetite or activity), with or without fever

• Focal findings of bone inflammation (eg, warmth, swelling, point tenderness) that typically progress over several days to a week

• Limitation of function (eg, limited use of an extremity; limp; refusal to walk, crawl, sit, or bear weight)

Osteomyelitis should also be suspected in children who are found to have bacteremia or an imaging study with characteristic findings during the evaluation of other conditions (eg, fever, trauma). (See 'Clinical suspicion' above.)

● The initial evaluation of children with suspected osteomyelitis includes complete blood count with differential, erythrocyte sedimentation rate, C-reactive protein, blood culture, and plain radiographs. (See 'Initial evaluation' above.)

● Plain radiographs may be sufficient to confirm a diagnosis of osteomyelitis. If needed, additional

evaluation generally includes advanced imaging with magnetic resonance imaging (MRI) or scintigraphy. If it is available, MRI is preferred to scintigraphy in view of its higher degree of sensitivity and spatial resolution; however, scintigraphy may be better if symptoms are poorly localized or multiple areas of involvement are suspected, and can often be performed without the need for sedation (table 1 and table 2). (See 'Advanced imaging' above.)

● Specimens for Gram stain and culture should be obtained from as many sites of infection as possible. Isolation of a pathogen from bone, periosteal collection, joint fluid, or blood confirms the diagnosis and speciation and susceptibility testing are essential for planning for the prolonged treatment required for osteomyelitis. (See 'Microbiology' above.)

● The diagnosis of osteomyelitis is confirmed by histopathologic evidence of inflammation in a surgical specimen of bone (picture 1A-C) (if obtained) or identification of a pathogen by culture or Gram stain in an aspirate of bone. (See 'Confirmed osteomyelitis' above.)

Osteomyelitis is unlikely if advanced imaging studies (usually MRI or scintigraphy) are normal. (See 'Osteomyelitis unlikely (advanced imaging studies normal)' above.)

● The differential diagnosis of osteomyelitis includes other infections, noninfectious conditions, and radiographic mimics (table 4). (See 'Differential diagnosis' above.)

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Topic 6067 Version 29.0

GRAPHICS

Imaging abnormalities in osteomyelitis

Imaging Abnormal findings modality

Plain radiograph* Deep soft tissue swelling (3 days after onset)

Periosteal reaction or elevation (10 to 21 days after onset)

Lytic sclerosis (≥1 month after onset)

Magnetic resonance Bone marrow inflammation (decreased signal in T1-weighted images; increased signal in T2- imaging weighted images)

Edema in marrow and soft tissues

Penumbra sign (high-intensity-signal transition zone between abscess and sclerotic bone marrow in T1-weighted images)

With gadolinium enhancement: absent blood flow, suggestive of necrosis or abscess

Three-phase bone Focal uptake of tracer in the third phase (delayed phase) scan

Computed Increased density of bone marrow tomography Cortex destruction

Periosteal reaction (new bone formation) formation

Periosteal purulence

Sequestra (devitalized, sclerotic bone)

Ultrasonography Fluid collection adjacent to bone without intervening soft tissue

Thickening of periosteum

Periosteal elevation

* The timing and typical sequence of radiographic changes may vary with the site of infection and age of the patient.

References: 1. Browne LP, Mason EO, Kaplan SL, et al. Optimal imaging strategy for community-acquired Staphylococcus aureus musculoskeletal infections in children. Pediatr Radiol 2008; 38:841. 2. Jaramillo D, Treves ST, Kasser JR, et al. Osteomyelitis and septic arthritis in children: Appropriate use of imaging to guide treatment. AJR Am J Roentgenol 1995; 165:399. 3. Saigal G, Azouz EM, Abdenour G. Imaging of osteomyelitis with special reference to children. Semin Musculoskelet Radiol 2004; 8:255. 4. Schmit P, Glorion C. Osteomyelitis in infants and children. Eur Radiol 2004; 14 Suppl 4:L44.

Graphic 96767 Version 3.0

Acute osteomyelitis

Courtesy of Jon Mader, MD.

Graphic 72714 Version 3.0

Early repair in acute osteomyelitis

Courtesy of Jon Mader, MD.

Graphic 62981 Version 3.0

Chronic osteomyelitis

Courtesy of Jon Mader, MD.

Graphic 53767 Version 4.0

Brodie abscess radiograph

Graphic 87102 Version 5.0

Progression of radiographic findings in a six-year-old boy with osteomyelitis of the fibula

(A) Plain radiographs (after one week of swelling and pain in the calf) were initially interpreted as normal. (B) A plain radiograph obtained four days after the initial films demonstrates periosteal reaction and cortical thickening. (C) T1 weighted magnetic resonance image with gadolinium demonstrates enhancement of the fibula marrow space and surrounding soft tissues.

Courtesy of Marvin B Harper, MD.

Graphic 50259 Version 4.0

Osteomyelitis with subperiosteal abscess

Radiograph of the femur demonstrates periosteal elevation due to a subperiosteal abscess as the result of osteomyelitis.

Courtesy of Marvin B Harper, MD.

Graphic 71349 Version 4.0

Lytic lucency in osteomyelitis

(A) Radiograph at the initial evaluation of a nine-year-old with fever and limp demonstrates a lytic lucency in the distal femoral metaphysis. (B, C) Axial and coronal magnetic resonance (MR) images delineate the area of osteomyelitis and adjacent marrow edema.

Graphic 51834 Version 5.0

Early osteomyelitis in a six-year-old with fever and ankle pain

Radiographs of the ankle (A) demonstrate deep soft tissue swelling (arrow) inferior to the medial malleolus. A technetium 99m bone scan shows increased uptake in the distal tibia in the blood flow (B) and bone uptake (C; four hour) phases.

Courtesy of Marvin B Harper, MD.

Graphic 77957 Version 4.0

Osteomyelitis in a nine-year-old girl with knee pain and fever

(A) Plain radiographs of the knee are unremarkable. (B) T1 weighted MRI demonstrates marked decrease in signal intensity in the medial metaphysis and epiphysis of the distal femur. There is some involvement of the soft tissue. (C) These findings are more pronounced in a T1 weighted MRI with gadolinium.

MRI: magnetic resonance imaging.

Courtesy of Marvin B Harper, MD.

Graphic 66132 Version 4.0

Comparison of imaging modalities in children with osteomyelitis

Modality Indications Advantages Disadvantages Comments*

Plain radiographs Baseline Inexpensive Abnormal findings Sensitivity 16 to 20 Excluding other Easy to obtain usually not present at percent conditions in onset of symptoms, Specificity 80 to 100 differential diagnosis except in newborns percent Monitoring disease Normal radiograph at progression onset does not exclude osteomyelitis

MRI¶ Identify location and No radiation risk Costly Sensitivity: 80 to 100 extent of disease Demonstrates early Less useful in percent Evaluation of adjacent changes in the multifocal or poorly Specificity: 70 to 100 structures for marrow cavity localized disease percent extension of infection Improved Requires more time Osteomyelitis unlikely (soft tissues, growth demonstration of than CT if MRI is normal plate, epiphysis, joint) subperiosteal abscess Young children may Evaluation of difficult Demonstration of require sedation or sites (eg, pelvis, concomitant septic anesthesia vertebral bodies, arthritis, venous Not always available intervertebral discs) thrombosis, or

Planning surgical pyomyositis intervention

Scintigraphy Poorly localized More useful than MRI Radiation exposure Sensitivity: 53 to 100 symptoms (eg, young in multifocal or poorly Does not provide percent children who cannot localized disease information about Specificity: 50 to 100 verbalize) Demonstrates early extent of purulent percent Multifocal disease changes collections that may Osteomyelitis unlikely Readily available require drainage if scintigraphy is May require less normal sedation than MRI May be falsely negative if blood supply to periosteum is interrupted (eg, subperiosteal abscess)

CT Evaluation of cortical Less time-consuming Expensive Sensitivity: 67 percent destruction, bone gas, than MRI Increased radiation Specificity: 50 percent and sequestrum Does not require exposure Generally used only if Delineating extent of sedation Poor soft tissue other studies are not bone injury in contrast possible or subacute/chronic inconclusive osteomyelitis Planning surgical interventions Evaluation of complications if MRI not available or contraindicated

Ultrasonography Evaluate fluid Inexpensive Does not penetrate Sensitivity: 55 percent collections in adjacent No radiation burden bone cortex Specificity: 47 percent structures (eg, joint, Noninvasive periosteum) Portable Monitor abscess resolution or progression

MRI: magnetic resonance imaging; CT: computed tomography. * Values for sensitivity and specificity are from: Dartnell J, Ramachandran M, Katchburian M. Haematogenous acute and

subacute paediatric osteomyelitis: A systematic review of the literature. J Bone Joint Surg Br 2012; 94:584. ¶ Preferred imaging study when imaging other than plain radiographs are necessary to establish the diagnosis of osteomyelitis.

References: 1. Dartnell J, Ramachandran M, Katchburian M. Haematogenous acute and subacute paediatric osteomyelitis: A systematic review of the literature. J Bone Joint Surg Br 2012; 94:584. 2. Faust SN, Clark J, Pallett A, Clarke NM. Managing bone and joint infection in children. Arch Dis Child 2012; 97:545. 3. Peltola H, Pääkkönen M. Acute osteomyelitis in children. N Engl J Med 2014; 370:352. 4. Yeo A, Ramachandran M. Acute haematogenous osteomyelitis in children. BMJ 2014; 348:g66.

Graphic 96521 Version 4.0

Magnetic resonance image distal femoral osteomyelitis and subperiosteal abscess

Axial (A) and coronal (B) magnetic resonance images (post gadolinium infusion) of a seven-year-old with distal femoral osteomyelitis and subperiosteal abscess. The abscess is posterior on the axial view (arrow) and medial to the distal femur on the coronal view (arrow). The pus is dark and surrounded by an enhancing rim.

Courtesy of William Phillips, MD, Texas Children's Hospital.

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Magnetic resonance image demonstrating osteomyelitis

(A) The proximal shaft and metaphysis of the left tibia show an abnormal mottled appearance. (B) The marrow signal from the left tibia is abnormal. In addition, there is soft tissue inflammation surrounding the left tibia.

Courtesy of Sheldon L Kaplan, MD. Texas Children's Hospital.

Graphic 59602 Version 3.0

Penumbra sign in osteomyelitis

Magnetic resonance imaging (MRI) scan shows the penumbra sign (a transitional zone with relatively high signal intensity between abscess and sclerotic bone marrow on T1-weighted MRI).

Graphic 56913 Version 11.0

Clinical features associated with bacterial pathogens that cause acute hematogenous osteomyelitis in children

Clinical features

Gram-positive bacteria

Staphylococcus aureus All ages; possible associated skin or soft tissue infection; MRSA may be associated with venous thromboembolism and pulmonary disease

Coagulase-negative Neonates in intensive care unit; children with indwelling vascular catheters (eg, for staphylococci chronic hemodialysis)

Group A Streptococcus More common in children younger than 4 years; may occur as a complication of concurrent varicella-zoster virus infection

Group B Streptococcus Infants younger than 3 months (usually 2 to 4 weeks)

Actinomyces May affect the facial bones, the pelvis, or vertebral bodies

Gram-negative bacteria

Kingella kingae Children 6 to 36 months; indolent onset; oral ulcers preceding musculoskeletal findings; may affect nontubular bones

Haemophilus influenzae type b Incompletely immunized children in areas with low Hib immunization rates

Bartonella henselae Children with cat exposure; may affect the vertebral column and pelvic girdle; may cause multifocal infection

Pseudomonas aeruginosa Injectable drug use

Brucella Travel to or living in an endemic area; ingestion of unpasteurized dairy products

Mycobacterium tuberculosis Birth in, travel to, or contact with a visitor from, a region endemic for M. tuberculosis

Nontuberculous mycobacteria Surgery or penetrating injury; CGD; other underlying immunodeficiency; HIV infection

Salmonella species Children with sickle cell disease or related hemoglobinopathies; exposure to reptiles or amphibians; children with gastrointestinal symptoms; children in developing countries

Polymicrobial infection More likely with direct inoculation (eg, penetrating trauma) or contiguous spread (eg, from skull, face, hands, feet)

MRSA: methicillin-resistant S. aureus; CGD: chronic granulomatous disease; Hib: H. influenzae type b.

Graphic 96510 Version 8.0

Differential diagnosis of osteomyelitis in children and adolescents

Condition Features that distinguish from osteomyelitis

Other infections

Septicemia MRI or scintigraphy studies lack abnormalities characteristic of Cellulitis osteomyelitis Septic arthritis Deep abscess Pyomyositis

Noninfectious conditions

Chronic nonbacterial osteomyelitis (eg, Multifocal lesions on imaging studies CRMO) Lack of response to antimicrobial therapy

Malignancy (eg, primary bone tumor, Intermittent symptoms leukemia) Lack of response to antimicrobial therapy Characteristic histopathology

Bone infarction in patients with Improvement with hydration and other supportive measures hemoglobinopathy

Vitamin C deficiency (scurvy) Dietary history of limited vitamin C intake Petechiae, ecchymoses, bleeding gums, coiled hair, hyperkeratosis

Gaucher disease Characteristic radiographic features Dysmorphic features on examination

Complex regional pain syndrome Autonomic dysfunction Normal erythrocyte sedimentation rate, C-reactive protein

Caffey disease (infantile cortical Characteristic histopathology hyperostosis)

Radiographic mimics*

Benign bone tumors:

Fibrous dysplasia Absence of acute symptoms Osteoid osteoma Lack of response to antimicrobial therapy Osteoblastoma Characteristic histopathology Chondroblastoma Chondromyxoid fibroma

Langerhans cell histiocytosis Characteristic histopathology

Malignant bone tumors:

Osteosarcoma Intermittent symptoms Lack of response to antimicrobial therapy Characteristic histopathology

MRI: magnetic resonance imaging; CRMO: chronic recurrent multifocal osteomyelitis. * Refer to UpToDate topics on benign bone tumors, Langerhans cell histiocytosis, and malignant bone tumors for additional information about the radiographic appearance of these conditions.

Graphic 96520 Version 3.0

Perifollicular abnormalities in scurvy

In this example, the perifollicular hyperkeratotic papules are quite prominent, with surrounding hemorrhage. These lesions have been misinterpreted as "palpable purpura," leading to the mistaken clinical diagnosis of vasculitis.

Graphic 64172 Version 2.0

Contributor Disclosures

Conflict of interest policy

Contributor Disclosures

Conflict of interest policy

Official reprint from UpToDate® www.uptodate.com ©2020 UpToDate, Inc. and/or its affiliates. All Rights Reserved. Print Options Print | Back Text References Graphics Hematogenous osteomyelitis in children: ManagementContributor Disclosures Author: Paul Krogstad, MD Section Editors: Sheldon L Kaplan, MD, William A Phillips, MD Deputy Editor: Mary M Torchia, MD

All topics are updated as new evidence becomes available and our peer review process is complete.

Literature review current through: Feb 2020. | This topic last updated: Feb 06, 2019.

INTRODUCTION

Osteomyelitis is an infection localized to bone. It is usually caused by microorganisms (predominantly bacteria) that enter the bone hematogenously. Other pathogenic mechanisms include direct inoculation (usually traumatic, but also surgical) or local invasion from a contiguous infection (eg, sinusitis, decubitus ulcers, deep wound infections, periodontal disease). Risk factors for nonhematogenous osteomyelitis include open fractures that require surgical reduction, implanted orthopedic hardware (such as pins or screws), and puncture wounds.

The management of hematogenous osteomyelitis in children will be discussed here. The epidemiology, microbiology, clinical features, evaluation, and diagnosis of osteomyelitis in children are discussed separately:

ONGOING DIAGNOSTIC EVALUATION

Radiographs usually are obtained in the initial evaluation of suspected osteomyelitis. However, because radiographs may be normal early in the course, empiric antimicrobial therapy may be initiated before radiographic confirmation with advanced imaging studies (eg, magnetic resonance imaging [MRI], scintigraphy) has been accomplished. (See "Hematogenous osteomyelitis in children: Evaluation and diagnosis", section on 'Normal plain radiographs'.)

For children with suspected osteomyelitis whose initial radiographs are normal, MRI or scintigraphy typically is performed within a few days to substantiate the diagnosis. If empiric antimicrobial therapy is initiated before definitive imaging studies, cultures should be obtained from blood and suspected foci of

https://www.uptodate.com/...rint?search=osteomyelitis&source=search_result&selectedTitle=4~150&usage_type=default&display_rank=4[19.03.2020 15:29:17] Hematogenous osteomyelitis in children: Management - UpToDate

infection (if possible). (See 'Pretreatment evaluation' below.)

MRI or scintigraphy (if available) may be useful for children whose initial radiographs demonstrated soft tissue changes and periosteal reaction without characteristic changes in bone mineral density. Characteristic findings on MRI or scintigraphy support the diagnosis of osteomyelitis (table 1). (See "Hematogenous osteomyelitis in children: Evaluation and diagnosis", section on 'Advanced imaging'.)

Osteomyelitis is unlikely among children who lack characteristic findings on MRI or scintigraphy. Other types of infection and noninfectious causes of bone pain must be reconsidered. (See "Hematogenous osteomyelitis in children: Evaluation and diagnosis", section on 'Differential diagnosis'.)

INDICATIONS FOR SURGERY

Surgical intervention may be required at the time of presentation or during antimicrobial therapy if children fail to respond as expected or magnetic resonance imaging (MRI) indicates extensive bone/soft tissue involvement that requires debridement [1-4]. Consultation with an orthopedist with pediatric expertise is recommended early in the clinical course. (See "Hematogenous osteomyelitis in children: Evaluation and diagnosis", section on 'Overview'.)

Indications for surgical intervention include:

● Need for drainage of subperiosteal and soft tissue abscesses and intramedullary purulence ● Debridement of contiguous foci of infection (which also require antimicrobial therapy) ● Excision of sequestra (ie, devitalized bone) ● Failure to improve after 48 to 72 hours of antimicrobial therapy (see 'Response to therapy' below)

Lesions requiring surgical intervention usually are diagnosed with MRI. Computed tomography scans and radiographs also may reveal evidence of sequestra or involucra (sheaths of periosteal bone that form around a sequestrum) and are sometimes useful to plan surgical intervention. (See "Hematogenous osteomyelitis in children: Evaluation and diagnosis", section on 'Advanced imaging'.)

ANTIMICROBIAL THERAPY

Indications — We recommend initiation of empiric antimicrobial therapy for most children with clinical features suggestive of osteomyelitis (eg, symptoms and signs of bone pain, elevated erythrocyte sedimentation rate [ESR]/C-reactive protein [CRP]) and:

● Characteristic imaging abnormalities (most commonly noted on initial magnetic resonance imaging [MRI]) (table 1) (see "Hematogenous osteomyelitis in children: Evaluation and diagnosis", section on 'Advanced imaging')

● Normal radiographs if advanced imaging is not immediately available (eg, within 24 hours) or

feasible, particularly if they are ill appearing or have signs of sepsis; characteristic radiographic features of osteomyelitis are not usually apparent on plain radiographs until 10 days after symptom onset (see 'Ongoing diagnostic evaluation' above and "Hematogenous osteomyelitis in children: Evaluation and diagnosis", section on 'Plain radiographs')

In children who are otherwise well or only mildly ill appearing, administration of empiric antibiotics may be delayed for 24 to 48 hours until cultures can be obtained via surgery or interventional radiography. The rationale for this delay is that cultures from intraoperative and interventional radiology procedures are less often positive with longer periods of antimicrobial therapy prior to obtaining these specimens [5,6].

Pretreatment evaluation — Before initiating empiric antimicrobial therapy, cultures should be obtained from blood and suspected foci of infection. A minimum of one blood culture (but preferably two) should be obtained. Empiric antimicrobial therapy is adjusted according to clinical response and culture and susceptibility results (if a pathogen is isolated). (See "Hematogenous osteomyelitis in children: Evaluation and diagnosis", section on 'Microbiology' and 'Pathogen-directed therapy' below.)

Infectious disease specialist consultation may be warranted for immunocompromised patients (eg, those with sickle cell disease, chronic granulomatous disease [CGD]) because they often have infections with challenging antimicrobial susceptibility profiles. (See 'Additional coverage for other pathogens' below.)

Empiric parenteral therapy — Antimicrobial therapy for osteomyelitis often is initiated before the diagnosis is confirmed. The risk of delaying treatment for bacteremic patients may be significant, particularly for those with community-associated Staphylococcus aureus. (See 'Outcome' below and "Hematogenous osteomyelitis in children: Epidemiology, pathogenesis, and microbiology", section on 'Staphylococcus'.)

Factors in choice of regimen — Initial antimicrobial therapy for acute hematogenous osteomyelitis usually is administered parenterally. The empiric regimen is determined by the most likely pathogens and antimicrobial susceptibilities based on epidemiologic factors, including the child's age (table 2), clinical features (table 3), whether the infection is life threatening, and organisms prevalent in the community (algorithm 1). An additional consideration is the future ease of transition to an oral regimen so that indwelling intravenous catheters can be avoided. Thus, single (versus multiple) drug intravenous therapy and having an effective, palatable, oral counterpart may prove beneficial, particularly if no pathogens are recovered by any cultures. (See 'Switch to oral therapy' below.)

Systematic reviews of randomized and observational studies have provided a general guide to the choice of antibiotics for acute osteomyelitis in children [7-10]. In individual studies, the clinical cure rates for acute hematogenous osteomyelitis in children generally are >95 percent when empiric therapy is chosen according to age, underlying medical condition, and organisms that are prevalent in the community. Most of the cases in the systematic reviews were confirmed to be caused by gram-positive pathogens (predominantly S. aureus), but a positive culture was not always required for study inclusion.

Children younger than three months — For empiric parenteral therapy in children younger than

three months with suspected osteomyelitis, we use a third- or fourth-generation cephalosporin combined with an antistaphylococcal agent (table 4). Third generation cephalosporins include cefotaxime (if available), ceftazidime, or ceftriaxone; cefepime is a fourth generation cephalosporin. Antistaphylococcal agents include vancomycin, nafcillin/oxacillin, or cefazolin; cefazolin is an option for infants age one to three months in whom central nervous system infection has been excluded. For infants with allergy or intolerance to cephalosporins (very uncommon in this age group), we suggest consultation with an expert in pediatric infectious diseases.

This empiric regimen provides coverage for the most common causes of hematogenous osteomyelitis in this age group: S. aureus, gram-negative bacilli, and group B Streptococcus. (See "Hematogenous osteomyelitis in children: Epidemiology, pathogenesis, and microbiology", section on 'Microbiology'.)

Cefotaxime is the preferred third-generation cephalosporin. If cefotaxime is not available, ceftazidime or the fourth-generation cephalosporin cefepime are the preferred alternatives. Ceftriaxone is another alternative for infants who are not receiving intravenous calcium-containing solutions [11] but generally is avoided in young infants because of the theoretic increased risk of kernicterus.

Vancomycin is the preferred initial antistaphylococcal agent for infants:

● Who have been in an intensive care unit for more than one week (increased risk for hospital- acquired methicillin-resistant S. aureus (MRSA) or coagulase-negative staphylococci)

● Whose mothers have or are suspected to have infection or colonization with community-acquired S. aureus (increased risk of methicillin resistance)

At some institutions, clindamycin is used as an alternative to vancomycin if less than 10 percent of S. aureus isolates are methicillin resistant and less than 10 percent are clindamycin resistant, and the infant has localized infection with no signs of sepsis. Other experts may use a different threshold for clindamycin resistance. (See 'Children three months and older' below.)

Children three months and older — Empiric intravenous antimicrobial therapy for children older than three months should be directed against S. aureus (the most common cause of hematogenous osteomyelitis in this age group) and other gram-positive organisms (eg, group A streptococci, Streptococcus pneumoniae). Broader empiric therapy may be necessary for special populations. (See 'Additional coverage for other pathogens' below.)

Agents that provide antistaphylococcal and antistreptococcal coverage include nafcillin/oxacillin, cefazolin, clindamycin, and vancomycin. We do not generally use trimethoprim-sulfamethoxazole (TMP- SMX) for suspected community-associated MRSA (CA-MRSA) osteomyelitis in children because of the limited data supporting its efficacy and the high rate of mild adverse events [12]. (See "Staphylococcus aureus in children: Overview of treatment of invasive infections".)

The choice of regimen depends on whether the infection is life threatening (eg, the child has signs of sepsis), the local prevalence of CA-MRSA, and the susceptibility of CA-MRSA to clindamycin [1,13,14].

Coverage for gram-positive pathogens

● Life-threatening infection – For gram-positive coverage in children ≥3 months with acute hematogenous osteomyelitis and life-threatening infection (eg, signs of sepsis), we suggest vancomycin plus either nafcillin or oxacillin; we provide empiric antimicrobial therapy for other pathogens as indicated. Nafcillin or oxacillin is the preferred therapy for methicillin-susceptible S. aureus (MSSA). For children unable to tolerate penicillins, we use vancomycin alone. (See 'Additional coverage for other pathogens' below.)

● Non-life-threatening infection – For gram-positive coverage in children ≥3 months with acute hematogenous osteomyelitis and non-life-threatening infection:

• We suggest nafcillin/oxacillin or cefazolin if <10 percent of the community S. aureus isolates are methicillin resistant. For children who are unable to tolerate penicillin and cephalosporin antibiotics, we suggest clindamycin if <10 percent of S. aureus isolates are clindamycin resistant. Other experts may use a different threshold for clindamycin resistance.

• We suggest either vancomycin or clindamycin if ≥10 percent of the community S. aureus isolates are methicillin resistant [13,14].

- We suggest vancomycin for children who have underlying frequent contact with the health care system or who were hospitalized in the past six months because these children have an increased risk of clindamycin resistance.

- We suggest vancomycin when ≥10 percent of S. aureus isolates in the community also are resistant to clindamycin (constitutive and inducible) [15,16]. Other experts may use a different threshold for clindamycin resistance. (See "Overview of antibacterial susceptibility testing", section on 'Inducible clindamycin resistance testing'.)

- We suggest clindamycin for children with localized infection and no signs of sepsis if clindamycin resistance is not a concern based on local patterns of antimicrobial drug resistance.

Alternatives to vancomycin or clindamycin when MRSA is a concern include linezolid or daptomycin (daptomycin only if the child is ≥1 year of age and has no concomitant pulmonary involvement) [13,14,17].

A 2013 systematic review of three randomized trials and 22 observational studies addressing the choice of antibiotics found limited evidence to definitively guide the choice of antibiotics for acute osteomyelitis in children [9]. There is evidence from a quasi-randomized trial that first-generation cephalosporins (eg, cefazolin) and clindamycin are similarly effective treatments for acute osteomyelitis in children >3 months of age in an area with a low prevalence of MRSA and Kingella kingae [18].

Additional coverage for other pathogens — It may be necessary to add empiric coverage for

pathogens other than S. aureus (and other gram-positives) when clinical or laboratory factors suggest a specific pathogen (table 3). (See "Hematogenous osteomyelitis in children: Epidemiology, pathogenesis, and microbiology", section on 'Microbiology'.)

● Preschool children in day care – K. kingae should be considered as a possible pathogen in children 6 to 36 months of age (especially those attending day care) and those with indolent osteomyelitis or a history of oral ulcers preceding the onset of musculoskeletal findings [19-27]. K. kingae usually is susceptible to cephalosporins (eg, cefazolin) but is consistently resistant to vancomycin and often resistant to clindamycin and antistaphylococcal penicillins (eg, oxacillin, nafcillin) [23,24].

We generally do not provide initial empiric coverage for K. kingae in young children because most cases of osteomyelitis in the United States are caused by S. aureus and other gram-positive pathogens. In addition, initial multidrug therapy may complicate transition to oral therapy if an organism is not identified in culture. K. kingae generally causes relatively mild musculoskeletal infections; chronic osteomyelitis and other complications requiring surgical interventions are rare [24,28,29].

For children between 6 and 36 months of age who require vancomycin or clindamycin for empiric coverage of CA-MRSA, empiric coverage for K. kingae with cefazolin may be added if the child does not improve as expected. Alternatively, cefazolin may be substituted for vancomycin or clindamycin if CA-MRSA is not identified in cultures of blood, bone, or soft tissue aspirates. (See 'Culture-negative osteomyelitis' below and "Hematogenous osteomyelitis in children: Epidemiology, pathogenesis, and microbiology", section on 'Microbiology'.)

● Incomplete Haemophilus influenzae type b immunization – We add coverage for H. influenzae type b (Hib) (eg, cefotaxime, ceftriaxone) in children <2 years who have not been fully immunized against Hib (table 5) who are from areas where Hib immunization rates are low. Coverage for Hib is not necessary for children from areas with high Hib immunization rates. Regional vaccination coverage estimates for children 19 to 35 months are available from the Centers for Disease Control and Prevention.

● Sickle cell disease or reptile exposure – We add empiric coverage for Salmonella and other gram- negative bacilli (eg, cefotaxime, ceftriaxone) for children with sickle cell disease. Salmonella is a common cause of osteomyelitis in children with sickle cell disease [30,31]. Salmonella should also be considered in children with osteomyelitis and reptile or amphibian exposure and/or gastrointestinal symptoms [32]. (See "Acute and chronic bone complications of sickle cell disease", section on 'Osteomyelitis and septic arthritis'.)

● Chronic granulomatous disease – Addition of a third-generation cephalosporin (eg, cefotaxime, ceftriaxone) to initial empiric therapy is prudent for patients with CGD. In individuals with CGD, osteomyelitis frequently is caused by unusual organisms (eg, Aspergillus and other fungi, Serratia species, and other filamentous or gram-negative bacteria), as well as staphylococci [33,34]. https://www.uptodate.com/...rint?search=osteomyelitis&source=search_result&selectedTitle=4~150&usage_type=default&display_rank=4[19.03.2020 15:29:17] Hematogenous osteomyelitis in children: Management - UpToDate

Debridement combined with voriconazole has proven successful in some patients with invasive bone Aspergillus [34]. (See "Chronic granulomatous disease: Pathogenesis, clinical manifestations, and diagnosis", section on 'Infections' and "Chronic granulomatous disease: Treatment and prognosis", section on 'Treatment'.)

● Recent gastrointestinal surgery or complex urinary tract anatomy – Addition of 1) a third- or fourth-generation cephalosporin (eg, cefotaxime, ceftriaxone, cefepime) or 2) an aminoglycoside (eg, gentamicin) to the initial empiric regimen may be warranted for patients with recent gastrointestinal surgery or complex urinary tract anatomy. Such patients are at risk for infection with enteric gram- negative organisms.

● Injection drug users – Organisms that cause infection among injection drug users (IDU) vary markedly between communities. Pseudomonas aeruginosa frequently has been reported among IDUs with osteomyelitis.

If P. aeruginosa osteomyelitis is a consideration, we suggest that ceftazidime be added to empiric antistaphylococcal therapy with vancomycin, nafcillin, or oxacillin; this combination covers other gram-negative bacilli as well as S. aureus. (See "Pseudomonas aeruginosa skin and soft tissue infections" and "Principles of antimicrobial therapy of Pseudomonas aeruginosa infections".)

Pathogen-directed therapy — The antimicrobial regimen can be tailored to a specific pathogen when culture and susceptibility results are available (table 6) [10]. Doses are provided in the table (table 4). Consultation with an expert in infectious diseases is suggested for children with an inadequate response to therapy, unusual organisms, and/or drug allergies.

Culture-negative osteomyelitis — No organism is identified in approximately 50 percent of children with suspected osteomyelitis [10]. The decision to continue empiric antibiotic therapy is based upon the initial clinical suspicion, advanced imaging studies, and response to empiric therapy. Most cases can be managed with regimens that are appropriate for culture-positive cases in a given geographical location, and failures of treatment are rare. We generally use therapy appropriate for MSSA (eg, cefazolin, nafcillin, oxacillin) and monitor for response to therapy. Other experts may use clindamycin, particularly in areas with high rates of CA-MRSA (if rates of clindamycin resistance are low). (See 'Response to therapy' below.)

However, before committing the child to a long course of antibiotic therapy, the differential diagnosis must be reconsidered and likely alternative diagnoses excluded. This is particularly important for children whose imaging studies remain negative. (See "Hematogenous osteomyelitis in children: Evaluation and diagnosis", section on 'Differential diagnosis'.)

Improvement with empiric therapy — For children who present with characteristic clinical and radiographic features of osteomyelitis and have negative cultures, but improve rapidly with empiric therapy, continuation of empiric antimicrobial therapy generally is warranted.

They may be switched to oral therapy focused on likely common pathogens (eg, S. aureus, Streptococcus pyogenes) if the clinical course is uncomplicated and they meet criteria for oral therapy. (See 'Switch to oral therapy' below.)

Continuation of empiric therapy directed toward gram-positive pathogens, particularly S. aureus, in children with culture-negative osteomyelitis is supported by a retrospective review in which outcomes were similar between 45 children with culture-positive osteomyelitis (42 percent with MSSA, 31 percent with MRSA) and 40 children with culture-negative osteomyelitis who received antistaphylococcal antibiotics [35]. A prospective study also found similar outcomes in 80 Finnish children with culture- negative osteoarticular infections who were treated with clindamycin or first-generation cephalosporins (8 also received amoxicillin or ampicillin) and 265 children with culture-positive osteoarticular infections (75 percent MSSA, 10 percent Hib, 9 percent S. pyogenes, and 5 percent S. pneumoniae) [36]. These findings may not be generalizable because the proportion of cases caused by MRSA varies geographically [10]; MRSA is commonly encountered in the United States. (See "Hematogenous osteomyelitis in children: Epidemiology, pathogenesis, and microbiology", section on 'Staphylococcus'.)

Given the possibility of MRSA osteomyelitis, with associated increased risk of complications, it is essential to monitor the clinical and inflammatory response to empiric antimicrobial therapy in children with culture-negative osteomyelitis. (See 'Response to therapy' below.)

Lack of improvement with empiric therapy — Lack of improvement or worsening during empiric parenteral antimicrobial therapy in children with clinical and radiographic features of osteomyelitis and negative cultures may indicate:

● Development of a complication (eg, periosteal or soft tissue abscess, venous thrombosis)

● Ineffective antimicrobial therapy (eg, unusual or resistant pathogen, polymicrobial infection, inadequate dose of antibiotic agent or failure to administer it)

● A diagnosis other than osteomyelitis

The evaluation and management of these possibilities is discussed below. (See 'Lack of improvement or worsening' below.)

Response to therapy

Monitoring response — The response to therapy is assessed with serial clinical, laboratory, and imaging evaluations (table 7). During hospitalization, we monitor:

● Clinical status (eg, fever, pain, localized erythema or swelling, new sites of infection) at least daily.

● CRP if clinical status worsens and every two to three days until CRP has demonstrated a >50 percent reduction or steady decline, then weekly.

CRP and ESR have both been used to monitor response in children with acute osteomyelitis.

However, the ESR typically increases during the first several days of treatment and consequently does not usually play a role in the management during the initial hospitalization. CRP also increases early in the infection but returns to normal much more rapidly than ESR (eg, one week versus three to four weeks in a systematic review [10]), which makes it more useful in monitoring the response to therapy [37-40]. Increase in CRP on or after the fourth day of treatment (if it is not associated with surgical interventions) may be associated with a complicated clinical course (eg, prolonged symptoms, progression of radiographic changes, need for repeat surgical intervention) [41-43]. (See "Hematogenous osteomyelitis in children: Clinical features and complications", section on 'Laboratory features'.)

● White blood cell (WBC) count before the switch to oral therapy if it was elevated at the time of diagnosis.

Elevations in the peripheral WBC count in children with hematogenous osteomyelitis are variable, present in only approximately one-third of patients [10], and nonspecific. The peripheral WBC count, if initially elevated, usually normalizes within 7 to 10 days after initiation of effective antimicrobial and/or surgical therapy.

● Radiographs if clinical status worsens or fails to improve (to evaluate development of complications; areas of devitalized bone [sequestra] become evident within two to four weeks); additional imaging, usually with MRI, may be necessary. (See 'Lack of improvement or worsening' below.)

Expected response — In children with acute hematogenous osteomyelitis who are receiving appropriate and effective antimicrobial therapy, clinical improvement usually occurs within three to four days. Clinical and laboratory improvement is indicated by:

● Resolution of fever

● Decreased pain and erythema or swelling

● Decrease in peripheral WBC (if initially elevated) and a drop in CRP of ≥50 percent every two to three days

Clinical and laboratory improvement suggests that the diagnosis and choice of antimicrobial therapy are correct; continued improvement may be an indication for outpatient therapy. (See 'Switch to oral therapy' below.)

Lack of improvement or worsening — Lack of improvement or worsening is defined by:

● Worsening pain or extension of infection (eg, to the adjacent soft tissues, joint)

● Persistent fever, pain, and discomfort with movement after five days in toddlers and seven days in older children and adolescents

● Failure of CRP to decline by ≥50 percent after one week of therapy and to continue to decline during

the second week [37]

● Progression of radiographic abnormalities in affected bones (eg, development of abscess, sequestra)

Patients who are not responding to treatment as expected require reevaluation and adjustment of therapy. Consultation with an expert in infectious diseases may be helpful if adjustments to antimicrobial therapy are indicated. Lack of improvement or worsening may indicate [2,4]:

● Development of a complication requiring surgical intervention (eg, soft tissue, subperiosteal, or intramedullary abscess; sinus tract; sequestra) (see 'Indications for surgery' above)

Prompt evaluation is warranted and may include ESR and/or CRP, WBC count, and plain radiograph of the affected area; further imaging, usually with MRI, may be necessary to identify a lesion requiring surgery [44]. Although repeat imaging may identify residual infection or other sites of infection, in children who have undergone surgical intervention, it can be difficult to distinguish postsurgical changes (eg, hematoma) from a recurrent abscess. (See 'Indications for surgery' above.)

● Thromboembolism (see "Venous thrombosis and thromboembolism in children: Risk factors, clinical manifestations, and diagnosis", section on 'Clinical manifestations')

● Ineffective antimicrobial therapy (eg, unusual or resistant pathogen, polymicrobial infection, inadequate dose of antibiotic)

An aggressive attempt must be made to isolate or identify fastidious (eg, K. kingae) and unusual pathogens (eg, Brucella, Bartonella henselae, fungi, mycobacteria) if appropriate exposures are identified (table 3).

A bone biopsy should be obtained for histopathologic staining and culture for bacteria, mycobacteria, and fungi; injection of bone aspirates or periosteal collections into blood culture bottles is recommended to enhance recovery of Kingella [45,46]. Polymerase chain reaction (if available) can be particularly helpful for detecting K. kingae in purulent materials or bone specimens [26]. (See "Hematogenous osteomyelitis in children: Epidemiology, pathogenesis, and microbiology", section on 'Microbiology' and "Hematogenous osteomyelitis in children: Evaluation and diagnosis", section on 'Microbiology'.)

Consultation with an expert in infectious diseases may be helpful if adjustments to antimicrobial therapy are indicated. Inclusion of coverage for K. kingae (eg, penicillin, cephalosporin) may be warranted for children between 3 and 36 months of age who were initially treated with vancomycin or clindamycin.

● A diagnosis other than osteomyelitis (see "Hematogenous osteomyelitis in children: Evaluation and diagnosis", section on 'Differential diagnosis')

Switch to oral therapy — There is no minimum duration of intravenous therapy for treatment of osteomyelitis [7]. Patients who are older than one month with uncomplicated osteomyelitis can be switched from intravenous to oral therapy after they have demonstrated unequivocal clinical improvement, as indicated by [47-49]:

● Lack of fever for ≥48 hours ● Decreased pain, erythema, or swelling ● Normalization of WBC count ● Consistent decrease in CRP

This usually occurs after 5 to 10 days of antimicrobial therapy [37,41,47,50,51].

Oral therapy avoids the risks of prolonged intravenous antibiotic administration via central venous catheters [52-54]. (See 'Response to therapy' above.)

In randomized trials and observational studies, treatment of osteomyelitis with intravenous antibiotics for short periods (approximately seven days) followed by oral therapy was as successful as longer courses of parenteral therapy [7,9,10,52,54].

● Prerequisites – Our prerequisites for switching to oral from parenteral therapy include:

• Age ≥1 month – The gastrointestinal absorption of oral antibiotics in neonates <1 month is unpredictable [55,56]; we provide their entire course of antimicrobial therapy parenterally.

• The clinical course has been uncomplicated.

• The child is immune competent and fully immunized against H. influenzae and S. pneumoniae for his or her age (table 5).

• If a pathogen is identified, it is susceptible to oral antibiotics.

• If cultures are negative, the child has responded as expected to empiric parenteral therapy and there is an oral regimen with a spectrum similar to the parenteral regimen.

• The child has demonstrated ability to swallow, retain, and absorb an appropriate oral medication; the initial doses of oral therapy should be administered while the child is in the hospital to ensure that the drug is tolerated.

• The patient and family have received appropriate education, are committed to the follow-up schedule, and are expected to adhere to the antimicrobial regimen.

Outpatient parenteral antimicrobial therapy (OPAT) may be warranted for patients with contraindications to oral therapy who have improved as expected with parenteral therapy. Insertion of a percutaneously inserted central catheter facilitates prolonged administration of parenteral antibiotics and can be used for OPAT. However, catheter-related complications (eg, malfunction, displacement, bloodstream infection) occur in 30 to 40 percent of children with osteoarticular

infections who are treated with OPAT [53,57].

Choice of oral regimen — The choice of oral therapy depends upon whether an organism was isolated from blood, bone (if obtained), or other culture. Additional considerations include bioavailability and palatability of the oral medication. Consultation with an expert in infectious diseases may be helpful in choosing the optimal oral agent, particularly if the child has an unusual pathogen or allergy to antibiotics.

When an organism is isolated, the susceptibility pattern can be used to determine an appropriate drug (table 6).

When an organism is not isolated, oral therapy is directed toward the most likely pathogen(s) given the child's age (table 2) and clinical presentation (table 3). The chosen regimen should have a spectrum similar to that provided by the parenteral therapy that was associated with improvement. As examples, a child who improved with cefazolin may be switched to cephalexin; a child who improved with parenteral clindamycin may be switched to oral clindamycin.

To ensure adequate bone penetration, antibiotics administered orally for hematogenous osteomyelitis generally are given in higher doses than those for treatment for other infections and recommended in package inserts (table 8) [47,58-60]. To achieve adequate serum levels, doses of beta-lactams (penicillins and cephalosporins other than cefixime) often can be increased to 100 to 150 mg/kg per day without serious adverse side effects.

We do not generally use oral TMP-SMX for CA-MRSA osteomyelitis in children because it has not been prospectively studied for this indication. However, there are some retrospective data that it may be effective [12].

Total duration

Confirmed or probable osteomyelitis — We suggest that children with confirmed or probable uncomplicated osteomyelitis be treated with antimicrobial therapy for a minimum of four weeks. The total duration for individual patients is determined by the clinical and radiographic response to therapy and normalization of inflammatory markers. (See "Hematogenous osteomyelitis in children: Evaluation and diagnosis", section on 'Diagnostic interpretation'.)

We administer antimicrobial therapy for four weeks and until the ESR and CRP are normal [1,47,50,61], whichever is longer, regardless of pathogen or complications. Other experts may not use normalization of ESR as a criterion for discontinuation of antimicrobial therapy or may document normalization of ESR only in children with osteomyelitis caused by MRSA [62] and in cases that have been initially complicated (eg, concomitant septic arthritis, intraosseous or periosteal abscess or lytic bone lesions at presentation, requiring repeated surgical management of soft tissue foci, delayed normalization of CRP beyond the expected 7 to 10 days).

Courses longer than four weeks may be necessary for children who require surgical debridement, have delayed clinical improvement or persistent elevation of CRP, have MRSA or Panton-Valentine leukocidin-

positive osteomyelitis, or have underlying medical conditions [10]. (See 'Outcome' below.)

Before discontinuing antimicrobial therapy, we also generally obtain a radiograph to make sure there are no new bone lesions (eg, devitalized bone [sequestra], lytic lesions), even if there is no clinical evidence of treatment failure. However, we discuss the need for and timing of subsequent radiographs with the pediatric orthopedist involved in the evaluation. Delaying the radiograph to allow initial or expected abnormalities to resolve is an alternative approach. (See 'Lack of improvement or worsening' above.)

A 2013 systematic review found limited evidence to strictly define the optimal duration of antimicrobial therapy for acute hematogenous osteomyelitis [9]. In the a randomized trial conducted in Finland, children with culture-proven osteomyelitis recovered completely whether they were treated for 20 or 30 days, provided that they had a good clinical response and rapid normalization of CRP [63]. However, the generalizability of these results is limited because there were minimal complications and 89 percent of cases were caused by MSSA. The proportion of cases caused by MRSA varies geographically but is common in the United States [38,39]. MRSA osteomyelitis requires increased duration of therapy, and some experts do not stop antimicrobial treatment until both the ESR and CRP have normalized. (See "Hematogenous osteomyelitis in children: Epidemiology, pathogenesis, and microbiology", section on 'Staphylococcus'.)

In observational studies, treatment failure appears to be more common with total duration ≤3 weeks than with treatment ≥4 weeks [7,48,64,65]. Consequently, we advise treatment for a minimum of four weeks and extend the duration if inflammatory markers and clinical findings remain abnormal.

Osteomyelitis unlikely — Osteomyelitis is unlikely if advanced imaging studies (usually MRI or scintigraphy) are normal. Decisions about continuation and duration of antimicrobial therapy should be made on a case-by-case basis. The results of the blood culture and response to antimicrobial therapy are important considerations in this decision.

● Positive blood culture, improvement with empiric therapy – Pathogen-directed antimicrobial therapy is warranted unless a source of infection other than osteomyelitis is identified. (See "Hematogenous osteomyelitis in children: Evaluation and diagnosis", section on 'Other infections'.)

● Positive blood culture, no improvement with empiric therapy – Continuation of pathogen- directed antimicrobial therapy is warranted pending evaluation for other sources of bacteremia and noninfectious conditions that may have predisposed the patient to bacteremia. (See "Hematogenous osteomyelitis in children: Evaluation and diagnosis", section on 'Differential diagnosis'.)

● Negative blood culture, improvement with empiric therapy – A shorter course of empiric antimicrobial therapy for a more superficial source of infection (eg, cellulitis) may be warranted. (See "Hematogenous osteomyelitis in children: Evaluation and diagnosis", section on 'Other infections'.)

● Negative blood culture, no improvement with empiric therapy – Empiric antimicrobial therapy usually can be discontinued; further investigation for pathogens not covered by empiric therapy may be necessary. Noninfectious causes of musculoskeletal pain should be sought. (See https://www.uptodate.com/...rint?search=osteomyelitis&source=search_result&selectedTitle=4~150&usage_type=default&display_rank=4[19.03.2020 15:29:17] Hematogenous osteomyelitis in children: Management - UpToDate

"Hematogenous osteomyelitis in children: Evaluation and diagnosis", section on 'Noninfectious conditions'.)

Drug monitoring

● Adverse effects – Children who are being treated with parenteral or oral antibiotic therapy for osteomyelitis require monitoring for potential adverse effects. Adverse effects of high-dose antibiotic therapy may include pancytopenia, leukopenia, hepatitis [66], impaired liver or renal function, and antibiotic-associated diarrhea [67,68].

The monitoring schedule varies depending upon the drug, dose, and route of therapy. We obtain complete blood count (CBC; with differential) weekly initially, while the patient is receiving beta- lactam antibiotics (eg, penicillins, cephalosporins). We also obtain a biochemical profile, including serum aminotransferases, weekly while the patient is receiving penicillin antibiotics or parenteral cephalosporins. Some experts also obtain laboratory studies every one to two weeks for clindamycin, although hematologic adverse effects are less of a concern. For linezolid, CBCs should be monitored weekly for therapy beyond two weeks. (See 'Follow-up' below.)

● Adequacy of therapy – We generally do not monitor concentrations of antimicrobial agents except for children receiving oral therapy whose clinical findings and inflammatory markers do not improve as expected. Rare patients have inadequate serum concentrations despite high oral doses [61]. We monitor adequacy of therapy and adherence by following ESR and CRP.

Although serum bactericidal titers have historically been used to monitor the adequacy of drug therapy, they are not widely available and require isolation of an organism [69].

OTHER THERAPIES

Immobilization — Immobilization of the affected extremity may relieve pain. It also may prevent pathologic fractures when bone involvement is extensive as detected by radiography or other imaging modalities. Immobilization may be particularly important for children with osteomyelitis of the proximal femur or vertebral osteomyelitis and children with methicillin-resistant S. aureus (MRSA) osteomyelitis [70].

We suggest protected weight-bearing and activity restriction for children with risk factors for pathologic fracture until inflammatory markers have returned to normal, the involved bone appears normal on radiographs, and the child is pain free. Risk factors for pathologic fracture include [70]:

● Prolonged hospital stay ● Multiple surgical procedures ● Maximum circumferential extent of abscess ≥50 percent of bone circumference on magnetic resonance imaging (MRI) ● https://www.uptodate.com/...rint?search=osteomyelitis&source=search_result&selectedTitle=4~150&usage_type=default&display_rank=4[19.03.2020 15:29:17] Hematogenous osteomyelitis in children: Management - UpToDate

Sharp zone of diminished marrow enhancement on MRI ● Infection caused by USA300-0114 MRSA pulsotype, including USA300 methicillin-susceptible S. aureus strains

Thromboembolism — Patients with associated deep vein thrombosis and/or septic pulmonary emboli are usually managed in conjunction with a hematologist. Management typically involves anticoagulation and continuation of antimicrobial therapy until the thrombus has resolved on Doppler imaging. (See "Venous thrombosis and thromboembolism in children: Treatment, prevention, and outcome", section on 'Anticoagulant agents'.)

FOLLOW-UP

Children who are being treated as outpatients for osteomyelitis with either intravenous or oral antibiotics should be seen at one- to two-week intervals. They should be monitored for continued clinical improvement and adverse effects of high-dose antibiotic therapy (eg, pancytopenia, leukopenia, impaired liver or renal function, antibiotic-associated diarrhea, pseudomembranous colitis). At each visit, we obtain C-reactive protein (CRP) and complete blood count (with differential); we also obtain a biochemical profile, including serum aminotransferases if the patient is receiving beta-lactam antibiotics (eg, penicillins, intravenous cephalosporins). (See 'Drug monitoring' above.)

For children with complicated osteomyelitis (eg, concomitant septic arthritis, intraosseous or periosteal abscess or lytic bone lesions at presentation, requiring repeated surgical management of soft tissue foci, delayed normalization of CRP [beyond the expected 7 to 10 days]), we obtain erythrocyte sedimentation rate when treatment discontinuation is being considered. We also generally obtain radiographs of the affected area(s) before discontinuation of antibiotics to make sure there are no new bone lesions. (See 'Total duration' above.)

No specific follow-up for uncomplicated osteomyelitis is necessary after discontinuation of antibiotics in children who have had an uneventful resolution of all clinical findings, although some surgeons may elect to follow children for 6 to 12 months to assess the growth of long bones, particularly those with complicated, extensive, or poorly responsive infections. This may be of particular importance if the growth plate (physis) was affected by the focus of infection. We counsel patients to seek attention if symptoms return in the area of initial confirmed or suspected osteomyelitis, noting that recrudescences may occur after prolonged periods of time. We also counsel families to watch for symptoms of Clostridioides (formerly Clostridium) difficile infection (eg, diarrhea, abdominal pain, abdominal distension). (See "Clostridioides (formerly Clostridium) difficile infection in children: Clinical features and diagnosis", section on 'Symptomatic disease'.)

OUTCOME

Most newborns, infants, and children who receive prompt, appropriate antimicrobial therapy before https://www.uptodate.com/...rint?search=osteomyelitis&source=search_result&selectedTitle=4~150&usage_type=default&display_rank=4[19.03.2020 15:29:17] Hematogenous osteomyelitis in children: Management - UpToDate

extensive bone necrosis develops have excellent outcomes. In systematic reviews and observational studies, >95 percent of patients have complete resolution of radiographically apparent bone damage [7,48,71].

The causative organism and location of infection may influence outcomes, particularly in neonates.

In a 2012 systematic review, risk factors for worse prognosis included [10]:

● Methicillin-resistant S. aureus (MRSA), S. pneumoniae, or Panton-Valentine leukocidin-positive S. aureus as the infecting organism ● Concurrent septic arthritis, pyomyositis, or abscess ● Involvement of the hip (40 percent risk of complications), ankle (33 percent complications), or knee (10 percent complications) [72] ● Positive culture ● Younger age (possibly related to delays in presentation, diagnosis, and treatment) ● Delay in treatment

Despite adequate therapy, recurrence of infection may occur in 1 to 2 percent of children with acute hematogenous osteomyelitis, and others may develop significant complications such as chronic osteomyelitis, limp, and leg length discrepancy [18,71].

Among neonates with osteomyelitis, the prognosis is generally better for group B streptococcal infection than staphylococcal infection [73,74]. Sequelae of neonatal osteomyelitis result from the extension of infection into the subperiosteal space and soft tissue, involvement of the growth plate, and the spread of infection into the adjacent joint space (figure 1). Destruction of the growth plate may be associated with growth disturbance (angular deformity, shortening or overgrowth of the affected bone) [75,76]. Other sequelae of neonatal osteomyelitis include osteonecrosis (avascular necrosis) of the femoral head and bony deformities. Among newborns with vertebral osteomyelitis, collapse or complete destruction of one or more vertebral bodies may occur, with kyphosis or spinal cord compression (and resultant paralysis) as late complications [77]. (See "Hematogenous osteomyelitis in children: Epidemiology, pathogenesis, and microbiology", section on 'Pathogenesis' and "Hematogenous osteomyelitis in children: Clinical features and complications", section on 'Complications'.)

Long-term sequelae are uncommon in older infants and children. However, multifocal disease, pathologic fractures, abnormal bone growth, chronic osteomyelitis, and the need for repeated surgical intervention have been reported frequently among patients with community-associated methicillin-resistant staphylococcal infection [59]. (See "Methicillin-resistant Staphylococcus aureus infections in children: Epidemiology and clinical spectrum", section on 'Community-onset'.)

In a case series of patients with S. aureus osteomyelitis from a single institution, 17 (4.7 percent) developed pathologic long-bone fractures; 15 of the 17 had MRSA [70]. Risk factors for pathologic fracture included prolonged hospital stay, multiple surgical procedures, large circumferential subperiosteal abscess (ie, maximum circumferential extent of abscess ≥50 percent of bone

circumference on magnetic resonance imaging [MRI]), sharp zone of diminished marrow enhancement on MRI, and USA300-0114 pulsotype. We suggest that children known to have these risk factors be managed with protected weight-bearing and activity restriction until inflammatory markers have returned to normal, the involved bone appears normal on radiographs, and the child is pain free.

CHRONIC OSTEOMYELITIS

Chronic osteomyelitis is defined by signs and symptoms of bone inflammation for at least two weeks and radiographic evidence of devitalized bone. Chronic osteomyelitis typically is described in patients with inadequate duration of therapy, but patient-specific etiologic and anatomic factors also play a role [48,78]. Chronic osteomyelitis is uncommon with current principles of management of acute hematogenous osteomyelitis.

Diagnosis of chronic osteomyelitis requires bone biopsy for culture and histopathologic confirmation. Bone biopsy also may be necessary to exclude other conditions that may have similar radiographic appearance, including nonbacterial osteomyelitis (eg, chronic recurrent multifocal osteomyelitis), Langerhans cell histiocytosis, large cell lymphoma, or primary bone tumors [79]. (See "Hematogenous osteomyelitis in children: Evaluation and diagnosis", section on 'Differential diagnosis'.)

Treatment of chronic osteomyelitis involves removing devitalized bone and long-term administration of antibiotics [79]. Repeated surgical debridement and bone grafting often are necessary. The importance of adequate surgical debridement and adequate dosing and duration of, and adherence to, antimicrobial therapy cannot be overemphasized.

The choice of antimicrobial agents and the duration of therapy have not been well studied [80], largely because chronic osteomyelitis is so rare in children. Antibiotic regimens that have been successful in small case series of patients with methicillin-susceptible S. aureus (MSSA) include oral cloxacillin (not available in the United States) combined with probenecid and nafcillin combined with oral rifampin [79,81,82]. In a 2010 systematic review, the success rate for treatment of chronic osteomyelitis due to various pathogens (predominantly S. aureus) ranged from 80 to 100 percent with parenteral therapy that ranged from 0.4 to 6 weeks and oral therapy from 0.2 to 4.3 months [80].

We suggest that children with chronic osteomyelitis caused by MSSA be treated with the combination of rifampin and a beta-lactam antibiotic (eg, penicillin or cephalosporin). For methicillin-resistant S. aureus, treatment with clindamycin is preferred (if the organism is susceptible). For culture-negative cases, treatment as for MSSA may be started, with careful clinical monitoring for improvement.

The duration of therapy is determined on a case-by-case basis. We typically obtain radiographs at monthly intervals and discontinue therapy after a four-week interval during which all bony changes are indicative of healing (eg, increased bone density, decrease in the size of lytic areas in bone).

Adjunctive measures, such as local irrigation with antimicrobial solutions with or without detergents and

surgical implantation of beads impregnated with antibiotics, have not been shown conclusively to affect outcome [83-86].

Complications of chronic osteomyelitis include joint stiffness, limb shortening, and pathologic fractures. (See "Hematogenous osteomyelitis in children: Clinical features and complications", section on 'Complications'.)

SOCIETY GUIDELINE LINKS

SUMMARY AND RECOMMENDATIONS

● In children with osteomyelitis, surgical intervention may be required at the time of presentation or during antimicrobial therapy. Indications for surgical intervention include:

• Drainage of subperiosteal and soft tissue abscesses and intramedullary purulence • Debridement of contiguous foci of infection • Excision of sequestra (ie, devitalized bone) • Failure to improve after 48 to 72 hours of antimicrobial therapy

Lesions requiring surgical intervention usually are diagnosed with radiography and magnetic resonance imaging (MRI). (See 'Indications for surgery' above.)

● For most children with clinical features compatible with osteomyelitis (eg, symptoms and signs of bone pain, elevated erythrocyte sedimentation rate [ESR]/C-reactive protein [CRP]), we recommend empiric antimicrobial therapy, even if the initial radiograph is normal (Grade 1B). Characteristic features of osteomyelitis are not usually apparent on radiographs until 10 days after symptom onset, and advanced imaging may not be immediately available or feasible. (See 'Indications' above.)

● Initial antimicrobial therapy for acute hematogenous osteomyelitis usually is administered parenterally. The empiric regimen is determined by the most likely pathogens and antimicrobial susceptibilities based on epidemiologic factors including the child's age (table 2), clinical features (table 3), and organisms prevalent in the community (algorithm 1). (See 'Empiric parenteral therapy' above.)

• For infants <3 months of age, we use a third-generation cephalosporin (eg, cefotaxime [preferred], ceftazidime, ceftriaxone, cefepime), plus an antistaphylococcal agent (usually vancomycin or nafcillin/oxacillin). Neonates who have been in an intensive care unit for more than one week should receive vancomycin rather than nafcillin/oxacillin. (See 'Children younger

than three months' above.)

• For children ≥3 months of age, we use cefazolin, nafcillin/oxacillin, clindamycin, or vancomycin, depending upon the local prevalence of community-associated methicillin-resistant Staphylococcus aureus (CA-MRSA) and the susceptibility of CA-MRSA to clindamycin. (See 'Children three months and older' above.)

• For children ≥3 months of age, it may be necessary to add empiric coverage for pathogens other than S. aureus when clinical or laboratory features suggest a specific pathogen (table 3). (See 'Additional coverage for other pathogens' above.)

● The antimicrobial regimen can be tailored to a specific pathogen when culture and susceptibility results are available (table 6). Children whose cultures remain negative and improve with empiric therapy usually are continued on the same parenteral regimen on which they improved, followed by an oral regimen with a similar spectrum. (See 'Pathogen-directed therapy' above and 'Culture- negative osteomyelitis' above.)

● Children receiving appropriate antimicrobial therapy generally demonstrate clinical improvement within three to four days. Clinical improvement is indicated by decreased fever, pain, erythema, swelling, peripheral white blood cell (WBC) count, and CRP. (See 'Expected response' above.)

● Lack of improvement or worsening may indicate development of a complication requiring surgical intervention (eg, abscess, sinus tract, sequestra), thromboembolism, ineffective antimicrobial therapy (eg, unusual or resistant pathogen, polymicrobial infection, insufficient dose), or a diagnosis other than osteomyelitis. Additional evaluation may include ESR/CRP, WBC count, plain radiography, and aggressive attempt to isolate fastidious and unusual pathogens. Adjustments to antimicrobial therapy may be necessary. (See 'Lack of improvement or worsening' above.)

● We administer antimicrobial therapy for a minimum of four weeks. Before discontinuing antimicrobial therapy, we recheck the CRP and the ESR, and we do not stop therapy if either is abnormal. We also generally obtain a radiograph to make sure there are no new bone lesions (eg, abscess, sequestra), even if there is no clinical evidence of treatment failure. (See 'Total duration' above.)

● Oral antibiotics may be used to complete the course of therapy for acute osteomyelitis in children older than one month who have unequivocal improvement (eg, afebrile for ≥48 hours, decreased pain and erythema or swelling, normalization of WBC count, consistent decrease in CRP), provided that (see 'Switch to oral therapy' above):

• The child is immune competent and fully immunized against Haemophilus influenzae and Streptococcus pneumoniae for age (table 5)

• The child demonstrates ability to swallow, retain, and absorb an appropriate oral medication

• The clinical course has been uncomplicated, including no progression of bone disease

• If a pathogen is identified, it is susceptible to oral antibiotics

• If cultures are negative, the child has responded as expected to empiric parenteral therapy and there is an oral regimen with a spectrum similar to the parenteral regimen

• The patient and family are expected to adhere to the medication and follow-up regimen

● After hospital discharge, children should be evaluated at one- to two-week intervals for clinical improvement and complications related to antibiotic therapy (table 7). Monitoring drug levels during oral therapy may be useful in selected patients (eg, those in whom resolution of clinical findings or normalization of CRP and ESR does not occur as expected). In addition, a radiograph should be performed at the end of treatment for children with complicated infections. (See 'Drug monitoring' above.)

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43. Amaro E, Marvi TK, Posey SL, et al. C-Reactive Protein Predicts Risk of Venous Thromboembolism in Pediatric Musculoskeletal Infection. J Pediatr Orthop 2019; 39:e62.

44. Courtney PM, Flynn JM, Jaramillo D, et al. Clinical indications for repeat MRI in children with acute hematogenous osteomyelitis. J Pediatr Orthop 2010; 30:883.

45. Yagupsky P. Kingella kingae: from medical rarity to an emerging paediatric pathogen. Lancet Infect Dis 2004; 4:358.

46. Centers for Disease Control and Prevention (CDC). Osteomyelitis/septic arthritis caused by Kingella kingae among day care attendees--Minnesota, 2003. MMWR Morb Mortal Wkly Rep 2004; 53:241.

47. Nelson JD, Bucholz RW, Kusmiesz H, Shelton S. Benefits and risks of sequential parenteral--oral cephalosporin therapy for suppurative bone and joint infections. J Pediatr Orthop 1982; 2:255.

48. Dich VQ, Nelson JD, Haltalin KC. Osteomyelitis in infants and children. A review of 163 cases. Am J Dis Child 1975; 129:1273.

49. Chou AC, Mahadev A. The Use of C-reactive Protein as a Guide for Transitioning to Oral Antibiotics in Pediatric Osteoarticular Infections. J Pediatr Orthop 2016; 36:173.

50. Nelson JD. Acute osteomyelitis in children. Infect Dis Clin North Am 1990; 4:513.

51. Arnold JC, Cannavino CR, Ross MK, et al. Acute bacterial osteoarticular infections: eight-year analysis of C-reactive protein for oral step-down therapy. Pediatrics 2012; 130:e821.

52. Zaoutis T, Localio AR, Leckerman K, et al. Prolonged intravenous therapy versus early transition to oral antimicrobial therapy for acute osteomyelitis in children. Pediatrics 2009; 123:636.

53. Ruebner R, Keren R, Coffin S, et al. Complications of central venous catheters used for the treatment of acute hematogenous osteomyelitis. Pediatrics 2006; 117:1210.

54. Keren R, Shah SS, Srivastava R, et al. Comparative effectiveness of intravenous vs oral antibiotics for postdischarge treatment of acute osteomyelitis in children. JAMA Pediatr 2015; 169:120.

55. Perkins MD, Edwards KM, Heller RM, Green NE. Neonatal group B streptococcal osteomyelitis and suppurative arthritis. Outpatient therapy. Clin Pediatr (Phila) 1989; 28:229.

56. Schwartz GJ, Hegyi T, Spitzer A. Subtherapeutic dicloxacillin levels in a neonate: possible mechanisms. J Pediatr 1976; 89:310.

57. Maraqa NF, Gomez MM, Rathore MH. Outpatient parenteral antimicrobial therapy in osteoarticular infections in children. J Pediatr Orthop 2002; 22:506.

58. Bryson YJ, Connor JD, LeClerc M, Giammona ST. High-dose oral dicloxacillin treatment of acute staphylococcal osteomyelitis in children. J Pediatr 1979; 94:673.

59. Martínez-Aguilar G, Hammerman WA, Mason EO Jr, Kaplan SL. Clindamycin treatment of invasive infections caused by community-acquired, methicillin-resistant and methicillin-susceptible Staphylococcus aureus in children. Pediatr Infect Dis J 2003; 22:593.

60. Landersdorfer CB, Bulitta JB, Kinzig M, et al. Penetration of antibacterials into bone: pharmacokinetic, pharmacodynamic and bioanalytical considerations. Clin Pharmacokinet 2009; 48:89.

61. Nelson JD. Toward simple but safe management of osteomyelitis. Pediatrics 1997; 99:883.

62. Belthur MV, Phillips WA, Kaplan SL, Weinberg J. Prospective evaluation of a shortened regimen of treatment for acute osteomyelitis and septic arthritis in children. J Pediatr Orthop 2010; 30:942.

63. Peltola H, Pääkkönen M, Kallio P, et al. Short- versus long-term antimicrobial treatment for acute hematogenous osteomyelitis of childhood: prospective, randomized trial on 131 culture-positive cases. Pediatr Infect Dis J 2010; 29:1123.

64. HARRIS NH. Some problems in the diagnosis and treatment of acute osteomyelitis. J Bone Joint Surg Br 1960; 42-B:535.

65. Blockey NJ, Watson JT. Acute osteomyelitis in children. J Bone Joint Surg Br 1970; 52:77.

66. Al-Homaidhi H, Abdel-Haq NM, El-Baba M, Asmar BI. Severe hepatitis associated with oxacillin therapy. South Med J 2002; 95:650.

67. Olson SC, Smith S, Weissman SJ, Kronman MP. Adverse Events in Pediatric Patients Receiving Long-Term Outpatient Antimicrobials. J Pediatric Infect Dis Soc 2015; 4:119.

68. Murphy JL, Fenn N, Pyle L, et al. Adverse Events in Pediatric Patients Receiving Long-term Oral and Intravenous Antibiotics. Hosp Pediatr 2016; 6:330.

69. Marshall GS, Mudido P, Rabalais GP, Adams G. Organism isolation and serum bactericidal titers in oral antibiotic therapy for pediatric osteomyelitis. South Med J 1996; 89:68.

70. Belthur MV, Birchansky SB, Verdugo AA, et al. Pathologic fractures in children with acute Staphylococcus aureus osteomyelitis. J Bone Joint Surg Am 2012; 94:34.

71. Karwowska A, Davies HD, Jadavji T. Epidemiology and outcome of osteomyelitis in the era of sequential intravenous-oral therapy. Pediatr Infect Dis J 1998; 17:1021.

72. Yeo A, Ramachandran M. Acute haematogenous osteomyelitis in children. BMJ 2014; 348:g66.

73. Edwards MS, Baker CJ, Wagner ML, et al. An etiologic shift in infantile osteomyelitis: the emergence of the group B streptococcus. J Pediatr 1978; 93:578.

74. Memon IA, Jacobs NM, Yeh TF, Lilien LD. Group B streptococcal osteomyelitis and septic arthritis. Its occurrence in infants less than 2 months old. Am J Dis Child 1979; 133:921.

75. Peters W, Irving J, Letts M. Long-term effects of neonatal bone and joint infection on adjacent growth plates. J Pediatr Orthop 1992; 12:806.

76. Williamson JB, Galasko CS, Robinson MJ. Outcome after acute osteomyelitis in preterm infants. Arch Dis Child 1990; 65:1060.

77. Overturf GD. Bacterial infections of the bone and joints. In: Infectious Diseases of the Fetus and Ne wborn, 7th ed, Remington JS, Klein JO, Wilson CB, et al (Eds), Elsevier Saunders, Philadelphia 20 11. p.296.

78. Riise ØR, Kirkhus E, Handeland KS, et al. Childhood osteomyelitis-incidence and differentiation from other acute onset musculoskeletal features in a population-based study. BMC Pediatr 2008; 8:45.

79. Ramos OM. Chronic osteomyelitis in children. Pediatr Infect Dis J 2002; 21:431.

80. Howard-Jones AR, Isaacs D. Systematic review of systemic antibiotic treatment for children with chronic and sub-acute pyogenic osteomyelitis. J Paediatr Child Health 2010; 46:736.

81. Bell SM. Further observations on the value of oral penicillins in chronic staphylococcal osteomyelitis. Med J Aust 1976; 2:591.

82. Norden CW, Bryant R, Palmer D, et al. Chronic osteomyelitis caused by Staphylococcus aureus: controlled clinical trial of nafcillin therapy and nafcillin-rifampin therapy. South Med J 1986; 79:947.

83. Makin M, Geller R, Jacobs J, Sacks T. Non-toxic detergent irrigation of chronic infections. An experimental evaluation. Clin Orthop Relat Res 1973; :320.

84. Anderson LD, Horn LG. Irrigation-suction technic in the treatment of acute hematogenous osteomyelitis, chronic osteomyelitis, and acute and chronic joint infections. South Med J 1970; 63:745.

85. Blaha JD, Calhoun JH, Nelson CL, et al. Comparison of the clinical efficacy and tolerance of gentamicin PMMA beads on surgical wire versus combined and systemic therapy for osteomyelitis. Clin Orthop Relat Res 1993; :8.

86. Walenkamp GH, Kleijn LL, de Leeuw M. Osteomyelitis treated with gentamicin-PMMA beads: 100 patients followed for 1-12 years. Acta Orthop Scand 1998; 69:518.

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GRAPHICS

Imaging abnormalities in osteomyelitis

Imaging Abnormal findings modality

Plain radiograph* Deep soft tissue swelling (3 days after onset)

Periosteal reaction or elevation (10 to 21 days after onset)

Lytic sclerosis (≥1 month after onset)

Magnetic resonance Bone marrow inflammation (decreased signal in T1-weighted images; increased signal in T2- imaging weighted images)

Edema in marrow and soft tissues

Penumbra sign (high-intensity-signal transition zone between abscess and sclerotic bone marrow in T1-weighted images)

With gadolinium enhancement: absent blood flow, suggestive of necrosis or abscess

Three-phase bone Focal uptake of tracer in the third phase (delayed phase) scan

Computed Increased density of bone marrow tomography Cortex destruction

Periosteal reaction (new bone formation) formation

Periosteal purulence

Sequestra (devitalized, sclerotic bone)

Ultrasonography Fluid collection adjacent to bone without intervening soft tissue

Thickening of periosteum

Periosteal elevation

* The timing and typical sequence of radiographic changes may vary with the site of infection and age of the patient.

Graphic 96767 Version 3.0

Most common causes of bacterial osteomyelitis in children according to age

Age group Most common bacterial etiologies

<3 months Staphylococcus aureus (MSSA and MRSA)

Group B Streptococcus (Streptococcus agalactiae)

Gram-negative bacilli

3 months to early S. aureus (MSSA and MRSA) childhood Group A Streptococcus (Streptococcus pyogenes)

Streptococcus pneumoniae

Kingella kingae*

Hib¶

Older children and S. aureus (MSSA and MRSA) adolescents Group A Streptococcus (S. pyogenes)

S. pneumoniae

MSSA: methicillin-susceptible S. aureus; MRSA: methicillin-resistant S. aureus; Haemophilus influenzae type b: Hib. * Usually 36 months of age or less. ¶ In children incompletely immunized against Hib.

Graphic 96519 Version 3.0

Clinical features associated with bacterial pathogens that cause acute hematogenous osteomyelitis in children

Clinical features

Gram-positive bacteria

Staphylococcus aureus All ages; possible associated skin or soft tissue infection; MRSA may be associated with venous thromboembolism and pulmonary disease

Coagulase-negative Neonates in intensive care unit; children with indwelling vascular catheters (eg, for staphylococci chronic hemodialysis)

Group A Streptococcus More common in children younger than 4 years; may occur as a complication of concurrent varicella-zoster virus infection

Group B Streptococcus Infants younger than 3 months (usually 2 to 4 weeks)

Actinomyces May affect the facial bones, the pelvis, or vertebral bodies

Gram-negative bacteria

Kingella kingae Children 6 to 36 months; indolent onset; oral ulcers preceding musculoskeletal findings; may affect nontubular bones

Haemophilus influenzae type b Incompletely immunized children in areas with low Hib immunization rates

Bartonella henselae Children with cat exposure; may affect the vertebral column and pelvic girdle; may cause multifocal infection

Pseudomonas aeruginosa Injectable drug use

Brucella Travel to or living in an endemic area; ingestion of unpasteurized dairy products

Mycobacterium tuberculosis Birth in, travel to, or contact with a visitor from, a region endemic for M. tuberculosis

Nontuberculous mycobacteria Surgery or penetrating injury; CGD; other underlying immunodeficiency; HIV infection

Salmonella species Children with sickle cell disease or related hemoglobinopathies; exposure to reptiles or amphibians; children with gastrointestinal symptoms; children in developing countries

Polymicrobial infection More likely with direct inoculation (eg, penetrating trauma) or contiguous spread (eg, from skull, face, hands, feet)

MRSA: methicillin-resistant S. aureus; CGD: chronic granulomatous disease; Hib: H. influenzae type b.

Graphic 96510 Version 8.0

Our approach to empiric antimicrobial therapy for children with acute hematogenous osteomy

This algorithm is intended for use with UpToDate content on management of osteomyelitis in children. Refer to UpToDate c additional aspects of management, including indications for surgical intervention.

ICU: intensive care unit; MRSA: methicillin-resistant S. aureus; Hib: Haemophilus influenzae type b; GI: gastrointestinal; MSSA: meth * Ceftriaxone is contraindicated in infants ≤28 days if they require or are expected to require treatment with intravenous solutions co ¶ Some experts also include cefazolin as an antistaphylococcal agent for infants age 1 to 3 months in whom central nervous system in Δ At some institutions, clindamycin is used as an alternative to vancomycin if <10% of S. aureus isolates are MRSA and the infant has ◊ Alternatives to vancomycin or clindamycin when MRSA is a concern include linezolid or daptomycin (daptomycin only if the child is ≥ involvement).

§ For children with life-threatening infections, the combination of vancomycin plus either nafcillin or oxacillin provides antibactericidal ¥ Consultation with an infectious disease specialist may be warranted for immunocompromised patients (eg, sickle cell disease, chron with unusual pathogens or resistance profiles. ‡ We consider the prevalence of MRSA in the community to be increased if ≥10% of S. aureus isolates are MRSA; other experts may † We consider the prevalence of clindamycin-resistant MRSA to be increased if ≥10% of MRSA isolates are resistant to clindamycin (c threshold. ** Refer to UpToDate content on prevention of Hib infection for details.

Graphic 120251 Version 2.0

Suggested doses of parenteral antibiotics commonly used in the treatment of osteoarticular infections in infants and children

Intravenous Dose for infants 8 to 28 days of age Dose for children >28 days of age agent

Ampicillin 150 mg/kg per day divided in 2 doses 200 to 400 mg/kg per day divided in 4 doses; maximum dose 12 g/day

Cefazolin 100 to 150 mg/kg per day divided in 3 doses 100 to 150 mg/kg per day divided in 3 doses; maximum dose 6 g/day

Cefepime 60 to 100 mg/kg per day divided in 2 doses 100 to 150 mg/kg per day divided in 3 doses; maximum dose 6 g/day

Cefotaxime 150 to 200 mg/kg per day divided in 3 doses 150 to 200 mg/kg per day divided in 3 or 4 doses; maximum dose 8 g/day

Ceftazidime 150 mg/kg per day divided in 3 doses 125 to 150 mg/kg per day divided in 3 doses; maximum daily dose 6 g

Ceftriaxone 50 to 75 mg/kg per day in 1 dose 75 to 100 mg/kg per day divided in 1 or 2 doses; maximum dose 4 g/day

Clindamycin 20 to 30 mg/kg per day divided in 3 doses 25 to 40* mg/kg per day divided in 3 or 4 doses; maximum dose 2.7 g/day

Daptomycin¶ NA 1 through 6 years: 12 mg/kg per day in 1 dose 7 through 11 years: 9 mg/kg per day in 1 dose 12 through 17 years: 7 mg/kg per day in 1 dose

Gentamicin 7.5 mg/kg per day divided in 3 doses 7.5 mg/kg per day divided in 3 doses

Linezolid 30 mg/kg per day divided in 3 doses <12 years: 30 mg/kg per day in 3 doses

≥12 years: 600 mg twice per day

Nafcillin 100 mg/kg per day divided in 4 doses 150 to 200 mg/kg per day divided in 4 doses; maximum dose 12 g/day

Oxacillin 100 mg/kg per day divided in 4 doses 150 to 200 mg/kg per day divided in 4 to 6 doses; maximum dose 12 g/day

Penicillin 150,000 units/kg per day divided in 3 doses 250,000 to 400,000 units/kg per day divided in 4 to 6 doses; maximum dose 24 million units per day

VancomycinΔ Loading dose of 20 mg/kg followed by 45 to 60 mg/kg per day divided in 3 to maintenance dose according to serum 4 doses; maximum dose 4 g/day creatinine as follows: <0.7 mg/dL: 15 mg/kg every 12 hours 0.7 to 0.9 mg/dL: 20 mg/kg every 24 hours 1.0 to 1.2 mg/dL: 15 mg/kg every 24 hours 1.3 to 1.6 mg/dL: 10 mg/kg every 24 hours >1.6 mg/dL: 15 mg/kg every 48 hours

Refer to UpToDate topics on management of osteomyelitis and septic arthritis in children for details regarding indications for particular drugs; recommended doses are for patients with normal renal function and infants born at >34 weeks' gestation. Consultation with an expert in pediatric infectious diseases is suggested for infants born at ≤34 weeks gestation.

NA: not available; IV: intravenous. *40 mg/kg per day is preferred for children ≥3 months of age. ¶ Daptomycin should not be used in children with concomitant pulmonary involvement and is not recommended in children <1 year of age because of the risk of potential effects on muscular, neuromuscular, and/or nervous systems (peripheral and/or central) observed in dogs. It is not approved for the treatment of osteoarticular infections in children; the appropriate dose for

osteoarticular infections has not yet been established but is the subject of clinical trials. The doses provided above are those that are recommended for Staphylococcus aureus bacteremia in children. Δ Dosing algorithm for vancomycin based upon serum creatinine concentration in neonates born at gestational age >28 weeks. A vancomycin dosing method based upon postnatal age and weight is provided as an alternative to the serum creatinine-based method listed above and may be useful in some clinical situations. This particular algorithm was provided in the 2009 edition of the Red Book.[1] Postnatal age <7 days: <1200 g: 15 mg/kg IV every 24 hours 1200 to 2000 g: 10 to 15 mg/kg IV every 12 or 18 hours >1200 g: 10 to 15 mg/kg IV every 8 or 12 hours Postnatal age ≥7 days: <1200 g: 15 mg/kg IV every 24 hours 1200 to 2000 g: 10 to 15 mg/kg IV every 8 or 12 hours >2000 g: 10 to 15 mg/kg IV every 6 or 8 hours

Data from: 1. American Academy of Pediatrics. Antibacterial drugs for newborn infants: Dose and frequency of administration. In: Red Book: 2009 Report of the Committee on Infectious Diseases, 28th ed, Pickering LK (Ed), American Academy of Pediatrics, Elk Grove Village, IL 2009. p.745. 2. American Academy of Pediatrics. Tables of antibacterial drug dosages. In: Red Book: 2018 Report of the Committee on Infectious Diseases, 31st ed, Kimberlin DW, Brady MT, Jackson MA, Long SS (Eds), American Academy of Pediatrics, Itasca, IL 2018. p.914. 3. Cubicin (daptomycin for injection). United States Prescribing Information. Revised September, 2017. US Food and Drug Administration. Available online at http://www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm (accessed August 3, 2018).

Graphic 51833 Version 23.0

◊

Suggested criteria for full Haemophilus influenza type b and Streptococcus pneumoniae immunization status when considering empiric antibiotics for community-acquired pneumonia in children

Current age* Criteria for full immunization¶

Haemophilus influenzae type b

12 to 15 months ≥2 doses of Hib conjugate vaccine, with at least one dose at ≥12 months of age

15 months to 5 years ≥2 doses of Hib conjugate vaccine, with at least one dose at ≥12 months of age, or

≥1 dose of Hib conjugate vaccine at ≥15 months of age

≥5 years, not high riskΔ Hib immunization not necessary

Streptococcus pneumoniae

12 to 24 months ≥3 doses of PCV at <16 months, with ≥1 dose at ≥12 months, or

2 doses of PCV, both at ≥12 months

24 months through 5 years ≥3 doses of PCV at <16 months, with ≥1 dose at ≥12 months, or

2 doses of PCV, both at ≥12 months, or

≥1 dose of PCV at ≥24 months

>5 years, not high risk◊ PCV immunization not necessary

Hib: H. influenzae type b; PCV: pneumococcal conjugate vaccine. * Children younger than 12 months are incompletely immunized against Hib and S. pneumoniae. ¶ Immunizations must be completed at least two weeks before pneumonia diagnosis. Δ Children at high risk for invasive Hib disease include chemotherapy recipients and those with anatomic or functional asplenia (including sickle cell disease), HIV infection, immunoglobulin deficiency, or early component complement deficiency. Please refer to the UpToDate topic on prevention of H. influenzae infection for a discussion of full Hib immunization in children at high risk for invasive Hib disease. ◊ Children at high risk for invasive S. pneumoniae disease include those with chronic heart disease (particularly cyanotic congenital heart disease and cardiac failure); chronic lung disease (including asthma if treated with high-dose oral corticosteroid therapy); diabetes mellitus; cerebrospinal fluid leak; cochlear implant; sickle cell disease and other hemoglobinopathies; anatomic or functional asplenia; HIV infection; chronic renal failure; nephrotic syndrome; diseases associated with treatment with immunosuppressive drugs or radiation therapy, including malignant neoplasms, leukemias, lymphomas, and Hodgkin disease; solid organ transplantation; or congenital immunodeficiency. Please refer to the UpToDate topics on PCVs and pneumococcal polysaccharide vaccines for a discussion of full S. pneumoniae immunization in children at high risk for invasive S. pneumoniae disease.

Graphic 95852 Version 6.0

Suggested antimicrobial regimens for the most commonly isolated pathogens causing osteoarticular infections in infants and children when results of culture and susceptibility testing are known

Parenteral Pathogen Oral agents agents

Staphylococcus aureus

Methicillin-susceptible Cefazolin Cephalexin Nafcillin Cloxacillin (not available in the United Oxacillin States) Dicloxacillin Clindamycin*

Methicillin-resistant

Clindamycin-susceptible Vancomycin Clindamycin Clindamycin

Clindamycin-resistant¶ Vancomycin Linezolid Linezolid DaptomycinΔ

Streptococcus agalactiae (Group B Penicillin Oral therapy not suggested in infants Streptococcus)

Streptococcus pyogenes (Group A Penicillin Penicillin Streptococcus) Ampicillin Amoxicillin

Streptococcus pneumoniae (Pneumococcus)

Penicillin-susceptible Penicillin Penicillin Amoxicillin

Penicillin-nonsusceptible Cefotaxime Clindamycin* Ceftriaxone Linezolid Clindamycin* Linezolid

Kingella kingae Penicillin Penicillin Cefazolin Cephalexin Cefotaxime Cefixime Ceftriaxone

Haemophilus influenzae type b Cefotaxime Amoxicillin (if susceptible) Ceftriaxone Cefixime Cefuroxime

* If isolate is clindamycin-susceptible. ¶ Clindamycin should not be used even if D-test is negative. Δ Daptomycin should not be used in children with concomitant pulmonary involvement. It is not approved for the treatment of osteoarticular infections in children; the appropriate dose has not been established.

Graphic 71347 Version 13.0

Our approach to monitoring response to treatment and adverse effects of therapy for osteomyelitis in children and adolescents

When to perform Comments

Clinical evaluation: At least daily during admission Worsening or failure to improve may Temperature Every 1 to 2 weeks after discharge indicate: Pain and range Development of a complication of movement Unusual or resistant pathogen Localized Polymicrobial infection swelling or Inadequate dose of antimicrobial agent, erythema or failure to administer it A diagnosis other than osteomyelitis

CRP and ESR CRP: During admission: Highly elevated CRP after ≥4 days of Every 2 to 3 days until ≥50% reduction treatment may be associated with prolonged or steady decline has occurred, then symptoms of progression of radiographic weekly if child remains hospitalized changes If clinical status worsens ESR is usually at its highest 2 to 3 days after Weekly during outpatient follow-up beginning antimicrobial therapy and declines slowly ESR: On admission and before stopping antimicrobial therapy* We continue antibiotic therapy for 4 weeks or until CRP and ESR are normal, whichever is longer*

CBC with differential Before switch to oral therapy if WBC count is The WBC count is elevated at diagnosis in elevated at time of diagnosis approximately one-third of children with osteomyelitis It usually normalizes within 7 to 10 days of initiation of effective antimicrobial therapy

Weekly in children receiving beta-lactam Adverse effects of beta-lactam drugs and antibiotics (eg, penicillins, cephalosporins)¶ linezolid include pancytopenia and Weekly for in children receiving linezolid for leukopenia >2 weeks

Serum antibiotic May be useful if poor absorption of antibiotic Rare patients have inadequate serum concentrationsΔ or failure to administer it are suspected concentrations despite high doses of antimicrobials

Biochemical profile Weekly if the patient is receiving penicillin Adverse effects of beta-lactam drugs include (including serum antibiotics or intravenous cephalosporins impaired liver or renal function, and aminotransferases) antibiotic-associated diarrhea

Radiographs If the clinical status worsens or fails to To assess complications: improve Soft tissue, subperiosteal, or intramedullary abscess Sinus tract Sequestra Pathologic fracture Additional imaging, usually with MRI, may be necessary

Before discontinuation of antimicrobial To ensure that there are no new bone therapy lesions (eg, devitalized bone, lytic lesions)

CRP: C-reactive protein; ESR: erythrocyte sedimentation rate; CBC: complete blood count; WBC: white blood cell; MRI: magnetic resonance imaging; MRSA: methicillin-resistant Staphylococcus aureus. * Some experts do not use normalization of ESR as a criterion for discontinuation of antimicrobial therapy or may document normalization of ESR only in children with osteomyelitis caused by MRSA and in cases that have been initially complicated (eg, concomitant septic arthritis, intraosseous or periosteal abscess or lytic bone lesions at presentation, requiring repeated surgical management of soft tissue foci, delayed normalization of CRP beyond the expected 7 to 10 days). ¶ Some experts also obtain monitoring every 1 to 2 weeks in children receiving clindamycin, although the risk of adverse hematologic effects is lower than with beta-lactam antibiotics.

Δ Expert opinion regarding monitoring of serum antibiotic concentrations varies. Some experts monitor serum concentrations only in children receiving oral therapy in whom CRP (and ESR, if measured) fails to normalize.

Graphic 119278 Version 3.0

◊

Doses of oral antibiotics commonly used in the treatment of osteoarticular infections in infants and children >1 month of age*

Oral agent Dose¶

Amoxicillin 100 mg/kg per day divided in 4 doses; maximum dose 4 g/day

Cefixime 8 mg/kg per day divided in 1 or 2 doses; maximum dose 400 mg/day

Cephalexin 100 to 150 mg/kg per day divided in 3 or 4 doses; maximum dose 4 g/day

Clindamycin 30 to 40Δ mg/kg per day divided in 3 doses; maximum dose 2.7 g/day

Cloxacillin◊ 125 mg/kg per day divided in 4 doses; maximum dose 4 g/day

Dicloxacillin§ 100 mg/kg per day divided in 4 doses; maximum dose 4 g/day

Linezolid <12 years: 30 mg/kg per day divided in 3 doses; maximum dose 1.8 g/day ≥12 years: 600 mg twice per day

Penicillin V 150 mg/kg per day divided in 6 doses; maximum dose 2 g/day

* Refer to UpToDate topics on treatment of bacterial arthritis and osteomyelitis in children for details regarding indications for particular drugs. ¶ Recommended doses are for patients with normal renal function. Beta-lactam antibiotics administered orally for osteoarticular infections generally are given in higher doses than those used for treatment of other infections and recommended in package inserts. Δ 40 mg/kg per day is preferred for children ≥3 months. ◊ Cloxacillin is not available in the United States. § Dicloxacillin suspension is no longer available.

Graphic 58533 Version 8.0

Developmental pathogenesis of acute osteomyelitis

Graphic 50672 Version 5.0

Contributor Disclosures

Conflict of interest policy

Official reprint from UpToDate® www.uptodate.com ©2020 UpToDate, Inc. and/or its affiliates. All Rights Reserved. Print Options Print | Back Text References Graphics Hematogenous osteomyelitis in children: Clinical featuresContributor and Disclosures complications

Author: Paul Krogstad, MD Section Editors: Sheldon L Kaplan, MD, William A Phillips, MD Deputy Editor: Mary M Torchia, MD

All topics are updated as new evidence becomes available and our peer review process is complete.

Literature review current through: Feb 2020. | This topic last updated: Feb 22, 2019.

INTRODUCTION

The clinical features and complications of hematogenous osteomyelitis in children will be discussed here. The epidemiology, microbiology, evaluation, diagnosis, and management of osteomyelitis in children are discussed separately:

● (See "Hematogenous osteomyelitis in children: Epidemiology, pathogenesis, and microbiology".) ● (See "Hematogenous osteomyelitis in children: Evaluation and diagnosis".) ● (See "Hematogenous osteomyelitis in children: Management".)

TERMINOLOGY

Osteomyelitis is an infection localized to bone. It is usually caused by microorganisms (predominantly bacteria) that enter the bone hematogenously.

Pathogenic mechanisms for nonhematogenous osteomyelitis include direct inoculation (usually traumatic, but also surgical) and local invasion from a contiguous infection (eg, cellulitis, decubitus ulcer, sinusitis, periodontal disease). Risk factors for nonhematogenous osteomyelitis include open fractures that require surgical reduction, implanted orthopedic hardware (such as pins or screws), bite wounds, and puncture wounds. (See "Infectious complications of puncture wounds".)

CLINICAL FEATURES

Clinical presentation — The initial symptoms of hematogenous osteomyelitis can be nonspecific in children of all ages (eg, malaise, low-grade fever). Once the infection becomes established in bone, symptoms are more localized. https://www.uptodate.com/...rint?search=osteomyelitis&source=search_result&selectedTitle=9~150&usage_type=default&display_rank=9[19.03.2020 15:33:08] Hematogenous osteomyelitis in children: Clinical features and complications - UpToDate

Children with hematogenous osteomyelitis usually present acutely with fever, constitutional symptoms (eg, irritability, decreased appetite or activity), focal findings of bone inflammation (warmth, swelling, point tenderness), and limitation of function (eg, limp, limited use of extremity) [1].

In a 2012 systematic review that included more than 12,000 children with acute and subacute osteomyelitis, presenting features included [2]:

● Pain – 81 percent ● Localized signs/symptoms – 70 percent ● Fever – 62 percent ● Reduced range of movement – 50 percent ● Reduced weight-bearing – 50 percent

Clinical features by age group — The clinical features of osteomyelitis are influenced by the characteristics of the developing skeleton. (See "Hematogenous osteomyelitis in children: Epidemiology, pathogenesis, and microbiology", section on 'Pathogenesis'.)

Birth to three months — Osteomyelitis is rare in newborns and young infants without underlying risk factors (eg, prematurity, skin infection, complicated delivery) [3,4]. Approximately one-half of cases are associated with antecedent infections, which often are health care-associated [5]. (See "Hematogenous osteomyelitis in children: Epidemiology, pathogenesis, and microbiology", section on 'Risk factors'.)

Symptoms of osteomyelitis in young infants may be mild and nonspecific [4]. Many infants lack focal findings, are afebrile, and continue to feed well, although they may have vomiting and irritability. Systemic symptoms may be more pronounced with Staphylococcus aureus osteomyelitis than with osteomyelitis caused by other pathogens. S. aureus osteomyelitis also may be associated with multifocal infection [5- 7].

Common initial signs include decreased movement, swelling, and/or erythema of the affected area. As the infection progresses, the epiphysis and adjacent joint may become involved. Soft tissue surrounding the infected bone may become swollen and discolored as purulence ruptures through the thin bony cortex into the contiguous muscle bed. (See "Hematogenous osteomyelitis in children: Epidemiology, pathogenesis, and microbiology", section on 'Birth to three months'.)

In a series of 30 infants (<4 months) with confirmed osteomyelitis, only 10 were febrile; five had no focal findings and were evaluated for osteomyelitis because of positive blood culture or suspected sepsis [4]. Concomitant septic arthritis occurred in 14 (42 percent) and multifocal infection in 12 (40 percent).

Older infants and toddlers — The initial symptoms of hematogenous osteomyelitis in older infants and young children frequently are nonspecific and mild. Verbal children may complain of localized pain. A history of nonspecific trauma may precede the onset of symptoms; diagnosis may be delayed if musculoskeletal complaints are initially attributed to trauma.

https://www.uptodate.com/...rint?search=osteomyelitis&source=search_result&selectedTitle=9~150&usage_type=default&display_rank=9[19.03.2020 15:33:08] Hematogenous osteomyelitis in children: Clinical features and complications - UpToDate

As the infection progresses, the child may refuse to use the affected extremity. Ambulatory young children with osteomyelitis of the lower extremity, pelvis, or spine may develop a progressive limp or refuse to sit, walk, or bear weight. Nonambulatory young children may refuse to sit or crawl, become irritable when picked up, or appear to be in pain or uncomfortable with diaper changing.

On examination, pain is typically well localized, with point tenderness over the infected bone; there may be contiguous edema. Pain is referred to the involved area when other parts of the long bone are percussed. In older infants and young children with vertebral osteomyelitis, there may be percussion tenderness over the contiguous spine, hip pain and stiffness, or loss of lumbar lordosis. However, it may be difficult to elicit these findings. Pelvic osteomyelitis may be localized to the buttock. In children with discitis, compression of the spine occasionally produces pain at the infected disc.

Older children and adolescents — In late childhood and adolescence, patients are more likely than younger children to complain of localized pain. Injury, rather than infection, may be suspected initially, particularly if the child is without fever and systemic symptoms, and may delay the diagnosis of osteomyelitis.

On physical examination, the infectious process is more anatomically confined than in younger children. There is less swelling of the surrounding soft tissue and less functional restriction. The point tenderness is more circumscribed, though pain is still referred to the involved area when other parts of the long bone are percussed. In older children and adolescents with vertebral osteomyelitis, there may be percussion tenderness over the contiguous spine, hip pain and stiffness, or loss of lumbar lordosis.

Severe staphylococcal sepsis and venous thrombosis have been described in some adolescents with osteomyelitis [8,9] (see 'Complications' below). However, adolescents with subacute/chronic osteomyelitis may have developed a localized, sclerotic, intraosseous abscess (Brodie abscess (image 1)) and typically present with insidious onset of mild to moderate long bone pain, with or without fever [10].

Site of infection — Hematogenous osteomyelitis generally occurs at only one site [1]. However, multifocal infection may occur, particularly in critically ill neonates and children with disease caused by community-associated methicillin-resistant S. aureus (CA-MRSA) or Bartonella henselae, or in children with sickle cell disease [4,8,11-13].

Long (tubular) bones are affected more frequently than nontubular bones (ie, flat, irregular, and sesamoid bones) (figure 1). Infection in nontubular bones occurs most often in the calcaneus and pelvis [2]. (See 'Chronic hemodialysis' below and "Hematogenous osteomyelitis in children: Epidemiology, pathogenesis, and microbiology", section on 'Microbiology'.)

Long (tubular) bones — More than 80 percent of cases of hematogenous osteomyelitis occur in the long (tubular) bones, usually originating in the metaphyses [2,14]. The femur and tibia are most frequently involved (figure 1).

Because the long bones are affected in the majority of cases, the clinical features of long-bone https://www.uptodate.com/...rint?search=osteomyelitis&source=search_result&selectedTitle=9~150&usage_type=default&display_rank=9[19.03.2020 15:33:08] Hematogenous osteomyelitis in children: Clinical features and complications - UpToDate

osteomyelitis are the "classic" presentation: focal findings of bone inflammation (warmth, swelling, point tenderness) and limitation of function (eg, limp, limited use of extremity) [15]. (See 'Clinical presentation' above.)

Spine — Infections of the spine can involve either the vertebral bodies or the intervertebral discs. Osteomyelitis of the spine should prompt consideration of Bartonella henselae and other unusual pathogens. (See 'Pathogen-specific features' below.)

Vertebral bodies — The vertebrae are involved in approximately 4 percent of cases of osteomyelitis in children [2,16]. Patients usually are older than eight years. They seek medical attention because of dull, constant back pain. They may appear toxic and markedly febrile after an indolent course with low-grade fever for two weeks' to several months' duration. Examination findings of vertebral osteomyelitis may include exquisite tenderness with percussion of the spinal dorsal process, spasm of the paraspinous muscles around the involved vertebrae, and pain with flexion or extension of the spine.

In a retrospective case series of 14 children with vertebral osteomyelitis, the mean age was 7.5 years and the mean duration of symptoms was 33 days [16]. At the time of initial presentation, 8 of the 14 complained of back pain, and 11 were febrile.

Vertebral osteomyelitis is rare in newborns and is difficult to diagnose. Although some infants may be highly febrile and toxic-appearing, most have nonspecific symptoms and signs that are often overlooked, even in closely monitored settings such as neonatal intensive care units [17]. The infant may eventually develop irritability when moved or have signs of infection at another site. Given the indolent presentation, vertebral osteomyelitis in newborns may be complicated by paraspinal abscess or collapse of one or more vertebral bodies, with secondary kyphosis or paralysis [17-19]. (See 'Complications' below.)

Intervertebral discs — Vertebral infections in children younger than five usually involve the intervertebral disc (discitis) rather than the vertebral body [16]. Discitis occurs almost exclusively in the lumbar regions. In young children, discitis typically presents with the gradual onset of irritability and back pain, limp, or refusal to crawl or walk, without systemic toxicity; fever usually is absent or low grade [16,20-22]. Abdominal pain and/or vomiting (secondary to ileus) may be the only complaints in children with involvement of T8 to L1. Most patients have had symptoms for three weeks or longer by the time discitis is diagnosed [16,20,23]. Examination findings may include percussion tenderness over the involved spine, hip pain and stiffness, loss of lumbar lordosis, neurologic findings (decreased muscle strength or reflexes), and ileus (with lesions of T8 to L1).

In a retrospective case series of 36 children with discitis, the mean age was 2.8 years and the mean duration of symptoms was 22 days [16]. At the time of presentation, 10 of the 36 were febrile, 23 of the 27 children <3 years of age had a limp or problems walking (eg, unsteady gait, refusal to walk, refusal to bear weight), and 6 of the 9 children ≥3 years of age complained of back pain.

Pelvis — Children with pelvic osteomyelitis often have symptoms referable to the hip, such as a gait abnormality or hip pain [24-26]. However, they also may localize the pain to the thigh, abdomen, lumbar

spine, or buttocks. Fever is frequently absent. Osteomyelitis of the pelvis is generally caused by S. aureus and other gram-positive pathogens, but unusual organisms (including Salmonella species and B. henselae) should be considered [26,27]. (See 'Pathogen-specific features' below.)

Unlike children with septic arthritis of the hip, children with pelvic osteomyelitis usually allow passive range of motion of the hip (which may be decreased). However, pain may be elicited by simultaneously putting the hip in flexion, abduction, and external rotation (figure 2). In addition, careful palpation and rectal examination may reveal areas of point tenderness [27].

The clinical features of pelvic osteomyelitis were described in a case series of 64 children from a single institution [26]:

● The average age was 11.5 years (range 1.2 to 17.5 years)

● Presenting symptoms included pain (95 percent), fever (47 percent), and altered weight-bearing (48 percent)

● The average duration of complaints was 13 days

● Examination findings included tenderness in 66 percent, fever in 39 percent, and decreased range of motion at the hip in 43 percent

● White blood cell (WBC) count was >12,000/microL in 30 percent (average 15,800/microL) and erythrocyte sedimentation rate was increased in 88 percent (average 44 mm/h)

● The ilium was involved most frequently

Similar findings were reported in a smaller case series and literature review [25].

Pathogen-specific features — The clinical features may vary depending upon the causative organism (table 1):

● In neonates, S. aureus osteomyelitis frequently is associated with systemic symptoms and multifocal infection. In contrast, group B Streptococcus usually affects a single bone without a clinically evident preceding infection.

● Osteomyelitis caused by CA-MRSA is more severe than osteomyelitis caused by other pathogens (eg, increased height and duration of fever, greater elevation of inflammatory markers, increased risk of complications, increased need for surgical intervention) [8,9,28-31].

● Panton-Valentine leukocidin (PVL)-positive isolates of S. aureus are associated with severe localized reaction and systemic inflammatory response (eg, greater elevation of inflammatory markers, increased frequency of bone destruction, increased need for surgical intervention) [28-31]. The specific role of PVL in the pathogenesis of osteomyelitis remains unclear; it may be a surrogate for other virulence factors [32].

● Osteomyelitis caused by group A Streptococcus is associated with higher fever (38.9°C [102°F]) than methicillin-susceptible S. aureus (38.1°C [100.6°F]) or pneumococcus (38.2°C [100.8°F]) [2].

● Kingella kingae osteomyelitis generally affects children between 6 and 36 months of age and is typically milder and more indolent than osteomyelitis due to other pathogens. In one series of 43 children with K. kingae osteoarticular infections, only 15 percent of children were febrile at presentation, and 39 percent had normal inflammatory markers [33]. K. kingae may disproportionately affect nontubular bones (eg, sternum, vertebrae, calcaneum) [34].

● B. henselae is a well-documented cause of osteomyelitis of the axial skeleton (skull, vertebral bodies, ribs, and pelvis) after a cat scratch or bite (although contact with cats may not be specifically recalled in proven cases); it also may cause multifocal disease [13,35,36].

● Compared with osteomyelitis cases in which an organism is not identified, culture-positive osteomyelitis is more frequently associated with a history of antecedent trauma; erythema, swelling, or frank cellulitis overlying the infected bone; a shorter duration of symptoms; and a higher WBC count [37,38].

● Coccidioidomycosis (an endemic mycosis due to Coccidioides immitis or Coccidioides posadasii) is a well-known cause of osteomyelitis in the southwestern United States; polyostotic disease is common, and the axial skeleton is frequently involved [39].

Special populations

Hemoglobinopathy — The clinical manifestations of hematogenous osteomyelitis in children with hemoglobinopathy (hemoglobin SS, S-beta thalassemia, hemoglobin SO-Arab, and certain children with hemoglobin SC) are similar to those in children without hemoglobinopathy. However, multiple sites may be involved, and it can be difficult to distinguish osteomyelitis from a vaso-occlusive crisis [40,41]. (See 'Clinical features' above and "Overview of variant sickle cell syndromes" and "Acute and chronic bone complications of sickle cell disease", section on 'Osteomyelitis and septic arthritis'.)

Chronic granulomatous disease — The clinical manifestations of osteomyelitis in children with chronic granulomatous disease may be minimal, even with well-established destructive lesions. They also may have recurrent episodes of osteomyelitis caused by bacterial and fungal pathogens. (See "Chronic granulomatous disease: Pathogenesis, clinical manifestations, and diagnosis", section on 'Infections'.)

Chronic hemodialysis — Children undergoing chronic hemodialysis are at greater risk for hematogenous osteomyelitis because of repeated invasions of their vascular compartment [42]. Indwelling intravenous cannulas can be colonized with coagulase-negative staphylococci or S. aureus, and osteomyelitis may develop. The thoracic spine and ribs are the bones most commonly involved; other tubular and cuboidal bones that have been traumatized also can become infected.

Central venous catheters — Rare cases of osteomyelitis have been described in children with

intestinal failure who are reliant upon indwelling central venous catheters and total parenteral nutrition. Osteomyelitis should be suspected when there are signs and symptoms of musculoskeletal infection [43].

LABORATORY FEATURES

The laboratory findings of children with osteomyelitis are described below. The laboratory evaluation for children with suspected osteomyelitis is discussed separately. (See "Hematogenous osteomyelitis in children: Evaluation and diagnosis", section on 'Initial evaluation'.)

● White blood cell count – Elevations in the peripheral white blood cell count (WBC) count in osteomyelitis are variable and nonspecific [44]. In a 2012 systematic review that included >12,000 patients, WBC count was elevated in only 36 percent of children at the time of presentation and normalized rapidly [2]. In a prospective study of 265 children with bone and joint infections (106 with osteomyelitis, 25 with osteomyelitis and septic arthritis), the mean WBC count was 12,600/microL at the time of presentation [45].

The WBC count tends to be higher and take longer to normalize in children with osteomyelitis caused by methicillin-resistant S. aureus (MRSA), group A Streptococcus, or Streptococcus pneumoniae and children with concomitant septic arthritis than in other clinical scenarios [46-50].

● Erythrocyte sedimentation rate – Elevation of the erythrocyte sedimentation rate (ESR) (≥20 mm/h) occurs in most children with osteomyelitis. In a 2012 systematic review, ESR was elevated in 91 percent of children at the time of presentation, peaked on day 3 to 5, and normalized over three to four weeks [2]. In a prospective study of 265 children with bone and joint infections (106 with osteomyelitis, 25 with osteomyelitis and septic arthritis), the mean ESR was 51 mm/h at the time of presentation [45].

The ESR tends to be higher and take longer to normalize in children with MRSA osteomyelitis and children with concomitant septic arthritis [46,47,51].

● C-reactive protein – Elevation of the C-reactive protein occurs in most children with osteomyelitis. In the 2012 systematic review, CRP was elevated in 81 percent of children at the time of presentation, peaked on day 2, and normalized over one week [2]. In a prospective study of 265 children with bone and joint infections (106 with osteomyelitis, 25 with osteomyelitis and septic arthritis), the mean CRP was 87 mg/L (8.7 mg/dL) at the time of presentation [45].

The CRP tends to be higher and take longer to normalize in children with MRSA osteomyelitis and children with concomitant septic arthritis [46,47,51-53].

RADIOGRAPHIC FEATURES

The radiographic features of osteomyelitis depend upon the imaging modality (table 2) [54]. Indications

for specific imaging modalities in children being evaluated for osteomyelitis are discussed separately (table 3). (See "Hematogenous osteomyelitis in children: Evaluation and diagnosis".)

● Radiographs – Radiographic findings associated with osteomyelitis include deep soft tissue swelling (image 2), periosteal reaction (suggestive of new bone formation or reactive edema), periosteal elevation (suggestive of subperiosteal abscess) (image 3), and lytic sclerosis (suggestive of subacute/chronic infection) (image 4).

● Magnetic resonance imaging – Magnetic resonance imaging abnormalities of osteomyelitis are apparent earlier than radiographic abnormalities [55]. Areas of active inflammation show a decreased signal in T1-weighted images and an increased signal in T2-weighted images [56]. Fat- suppression sequences, including short tau inversion recovery, decrease the signal from fat and are more sensitive for the detection of bone marrow edema. The penumbra sign (high-intensity-signal transition zone between abscess and sclerotic bone marrow in T1-weighted images (image 5)) is characteristic of osteomyelitis [57].

● Scintigraphy – Focal uptake of tracer in the third phase of a three-phase bone scan is associated with osteomyelitis.

● Computed tomography – Computed tomography findings of osteomyelitis include increased density of bone marrow, cortex destruction, periosteal reaction (new bone formation), periosteal purulence, and sequestra.

● Ultrasonography – Ultrasonography findings compatible with osteomyelitis include fluid collection adjacent to the bone without intervening soft tissue, elevation of the periosteum by more than 2 mm, and thickening of the periosteum.

DIAGNOSIS

The evaluation and diagnostic approach to hematogenous osteomyelitis in children are discussed in detail separately. Diagnostic criteria are summarized below. (See "Hematogenous osteomyelitis in children: Evaluation and diagnosis".)

The diagnosis is probable in a child with compatible clinical, laboratory, and/or radiologic findings (table 2) in whom a pathogen is isolated from blood, periosteal collection, or joint fluid. We also consider the diagnosis to be probable in a child with compatible clinical, laboratory, and radiologic findings and negative cultures if he or she responds as expected to empiric antimicrobial therapy.

The diagnosis is unlikely if advanced imaging studies (usually magnetic resonance imaging or

scintigraphy) are normal.

COMPLICATIONS

Musculoskeletal — Musculoskeletal complications of osteomyelitis vary with age, site of involvement, pathogen, and duration of infection. They include [13,17-19,58-62]:

● Extension of infection into the soft tissue (eg, pyomyositis), common in young infants.

● Septic arthritis if infection spreads to the joint space (more common with infections of the proximal humerus and femur) or with hematogenous delivery of organisms to the joint space (image 6).

● Abnormal bone growth (angular deformity, shortening (image 7A), or overgrowth (image 7B)) with involvement of the physis and epiphysis (more common in newborns and community-acquired methicillin-resistant S. aureus [CA-MRSA] infections).

● Subperiosteal abscess (image 3).

● Brodie abscess (image 1).

● Pathologic fracture (more common with CA-MRSA) [63].

● Multifocal infection (more common with CA-MRSA or B. henselae and in newborns).

● Osteonecrosis (avascular necrosis) of the femoral head.

● Collapse or complete destruction of one or more vertebral bodies, which may be associated with kyphosis or spinal cord compression.

● Devitalized bone (sequestra) and cutaneous fistulae.

● Chronic osteomyelitis (radiographic evidence of devitalized bone and ≥2 weeks of signs and symptoms of bone inflammation) occasionally occurs in a child who has longstanding musculoskeletal complaints that are not recognized as osteomyelitis [64]. However, it is usually described in patients with inadequate duration of therapy. (See "Hematogenous osteomyelitis in children: Management", section on 'Chronic osteomyelitis'.)

Venous thrombosis — Venous thrombosis and septic emboli may occur in older children and adolescents with osteomyelitis (image 8) [9,65-68]. Although the pathogenesis is uncertain, small observational studies suggest that venous thrombosis and septic emboli in children with osteomyelitis are associated with [9,65,67-69]:

● Age ≥8 years

● Occurrence at sites adjacent to the osteomyelitis

● https://www.uptodate.com/...rint?search=osteomyelitis&source=search_result&selectedTitle=9~150&usage_type=default&display_rank=9[19.03.2020 15:33:08] Hematogenous osteomyelitis in children: Clinical features and complications - UpToDate

S. aureus osteomyelitis, particularly MRSA and Panton-Valentine leukocidin-positive strains

● Coagulation abnormalities (eg, heterozygous for factor V Leiden mutation, increased antiphospholipid antibodies or factor VIII concentrations, positive lupus anticoagulant), some of which were transient

● Disseminated infection

● C-reactive protein >60 mg/L (6 mg/dL) at presentation

● Increased severity of infection (eg, longer hospitalization, more surgical procedures)

SOCIETY GUIDELINE LINKS

SUMMARY

● The initial symptoms of osteomyelitis can be nonspecific (eg, malaise, low-grade fever) in children of all ages. Once the infection becomes established in bone, symptoms are more localized. Children with osteomyelitis usually present with fever, constitutional symptoms (irritability, decreased appetite, decreased activity), focal findings of bone inflammation (warmth, swelling, point tenderness), and limitation of function (eg, limp, limited use of extremity). (See 'Clinical presentation' above.)

● Clinical features may vary with age:

• In young infants (zero to three months of age), initial clinical features may be mild and nonspecific. Bone infection may spread to the adjacent soft tissues and joints. (See 'Birth to three months' above.)

• In older infants and young children, clinical features may include limp; refusal to crawl, walk, sit, or bear weight; irritability when picked up; point tenderness over the infected bone; and contiguous edema. (See 'Older infants and toddlers' above.)

• In older children and adolescents, clinical features may include complaints of localized pain and focal examination findings (point tenderness). (See 'Older children and adolescents' above.)

● Children with osteomyelitis of the vertebral bodies usually are older than eight years and complain of dull, constant back pain. Examination findings may include tenderness with percussion of the spinal dorsal process, spasm of the paraspinous muscles around the involved vertebrae, and pain with flexion or extension of the spine. (See 'Spine' above.)

● Discitis is more common in children younger than five years and usually occurs in the lumbar regions. Clinical features include gradual onset of irritability and back pain, limp, or refusal to crawl or walk, without systemic toxicity. Examination findings may include percussion tenderness over the involved spine, hip pain and stiffness, loss of lumbar lordosis, neurologic findings (decreased muscle strength or reflexes), and ileus (with lesions of T8 to L1). (See 'Spine' above.)

● Children with pelvic osteomyelitis may complain of hip pain or gait abnormality, but also may localize pain to the thigh, abdomen, lumbar spine, or buttocks. Examination findings may include point tenderness and pain when the hip is simultaneously flexed, abducted, and externally rotated. (See 'Pelvis' above.)

● Laboratory features of osteomyelitis include elevations in erythrocyte sedimentation rate and C- reactive protein. Most patients do not have an elevated peripheral white blood cell count at the time of presentation. (See 'Laboratory features' above.)

● Radiographic features of osteomyelitis depend upon the imaging modality (table 2). (See 'Radiographic features' above.)

● Complications of osteomyelitis include extension of infection into the soft tissues, septic arthritis, abnormal bone growth (image 7A-B), subperiosteal or intraosseous abscess, pathologic fracture, devitalized bone, chronic osteomyelitis, and venous thrombosis. (See 'Complications' above.)

● The evaluation and diagnosis of hematogenous osteomyelitis in children are discussed separately. (See "Hematogenous osteomyelitis in children: Evaluation and diagnosis".)

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52. Unkila-Kallio L, Kallio MJ, Peltola H. The usefulness of C-reactive protein levels in the identification of concurrent septic arthritis in children who have acute hematogenous osteomyelitis. A comparison with the usefulness of the erythrocyte sedimentation rate and the white blood-cell count. J Bone Joint Surg Am 1994; 76:848.

53. Arnold SR, Elias D, Buckingham SC, et al. Changing patterns of acute hematogenous osteomyelitis and septic arthritis: emergence of community-associated methicillin-resistant Staphylococcus aureus. J Pediatr Orthop 2006; 26:703.

54. Schmit P, Glorion C. Osteomyelitis in infants and children. Eur Radiol 2004; 14 Suppl 4:L44.

55. Saigal G, Azouz EM, Abdenour G. Imaging of osteomyelitis with special reference to children. Semin Musculoskelet Radiol 2004; 8:255.

56. Guillerman RP. Osteomyelitis and beyond. Pediatr Radiol 2013; 43 Suppl 1:S193.

57. Shih HN, Shih LY, Wong YC. Diagnosis and treatment of subacute osteomyelitis. J Trauma 2005; 58:83.

58. Peters W, Irving J, Letts M. Long-term effects of neonatal bone and joint infection on adjacent growth plates. J Pediatr Orthop 1992; 12:806.

59. Williamson JB, Galasko CS, Robinson MJ. Outcome after acute osteomyelitis in preterm infants. Arch Dis Child 1990; 65:1060.

60. Overturf GD. Bacterial infections of the bone and joints. In: Infectious Diseases of the Fetus and Ne wborn, 7th ed, Remington JS, Klein JO, Wilson CB, et al (Eds), Elsevier Saunders, Philadelphia 20 11. p.296.

61. Martínez-Aguilar G, Hammerman WA, Mason EO Jr, Kaplan SL. Clindamycin treatment of invasive infections caused by community-acquired, methicillin-resistant and methicillin-susceptible Staphylococcus aureus in children. Pediatr Infect Dis J 2003; 22:593.

62. McNeil JC, Forbes AR, Vallejo JG, et al. Role of Operative or Interventional Radiology-Guided

Cultures for Osteomyelitis. Pediatrics 2016; 137.

63. Belthur MV, Birchansky SB, Verdugo AA, et al. Pathologic fractures in children with acute Staphylococcus aureus osteomyelitis. J Bone Joint Surg Am 2012; 94:34.

64. Ramos OM. Chronic osteomyelitis in children. Pediatr Infect Dis J 2002; 21:431.

65. Gorenstein A, Gross E, Houri S, et al. The pivotal role of deep vein thrombophlebitis in the development of acute disseminated staphylococcal disease in children. Pediatrics 2000; 106:E87.

66. Walsh S, Phillips F. Deep vein thrombosis associated with pediatric musculoskeletal sepsis. J Pediatr Orthop 2002; 22:329.

67. Crary SE, Buchanan GR, Drake CE, Journeycake JM. Venous thrombosis and thromboembolism in children with osteomyelitis. J Pediatr 2006; 149:537.

68. Hollmig ST, Copley LA, Browne RH, et al. Deep venous thrombosis associated with osteomyelitis in children. J Bone Joint Surg Am 2007; 89:1517.

69. Ligon JA, Journeycake JM, Josephs SC, et al. Differentiation of Deep Venous Thrombosis Among Children With or Without Osteomyelitis. J Pediatr Orthop 2018; 38:e597.

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GRAPHICS

Brodie abscess radiograph

Graphic 87102 Version 5.0

Sites of involvement in acute hematogenous osteomyelitis in children

Tubular bones are affected more frequently than nontubular (flat) bones or spine.

* This does not include the osteomyelitis of the calcaneum, which accounts for 5% of cases.

Data from: Dartnell J, Ramachandran M, Katchburian M. Haematogenous acute and subacute paediatric osteomyelitis: a systematic review of the literature. J Bone Joint Surg Br 2012; 94:584.

Graphic 61415 Version 4.0

FABERE test (Patrick test, "figure of four" test)

The FABERE test (Patrick test or "figure of four" test) consists of Flexion of the hip and knee, with ABduction and External Rotation at the hip, so that the ankle of one leg is on top of the opposite knee (a figure four configuration). Force is applied downwards on the bent knee and the opposite hip, causing Extension at the sacroiliac joint ipsilateral to the bent leg. Pain in the sacral region from pelvic torque during the FABERE test, in the absence of pain with passive motion of the hip joint, suggests discomfort arising from the sacroiliac joint.

Graphic 79475 Version 5.0

Clinical features associated with bacterial pathogens that cause acute hematogenous osteomyelitis in children

Clinical features

Gram-positive bacteria

Staphylococcus aureus All ages; possible associated skin or soft tissue infection; MRSA may be associated with venous thromboembolism and pulmonary disease

Coagulase-negative Neonates in intensive care unit; children with indwelling vascular catheters (eg, for staphylococci chronic hemodialysis)

Group A Streptococcus More common in children younger than 4 years; may occur as a complication of concurrent varicella-zoster virus infection

Group B Streptococcus Infants younger than 3 months (usually 2 to 4 weeks)

Actinomyces May affect the facial bones, the pelvis, or vertebral bodies

Gram-negative bacteria

Kingella kingae Children 6 to 36 months; indolent onset; oral ulcers preceding musculoskeletal findings; may affect nontubular bones

Haemophilus influenzae type b Incompletely immunized children in areas with low Hib immunization rates

Bartonella henselae Children with cat exposure; may affect the vertebral column and pelvic girdle; may cause multifocal infection

Pseudomonas aeruginosa Injectable drug use

Brucella Travel to or living in an endemic area; ingestion of unpasteurized dairy products

Mycobacterium tuberculosis Birth in, travel to, or contact with a visitor from, a region endemic for M. tuberculosis

Nontuberculous mycobacteria Surgery or penetrating injury; CGD; other underlying immunodeficiency; HIV infection

Salmonella species Children with sickle cell disease or related hemoglobinopathies; exposure to reptiles or amphibians; children with gastrointestinal symptoms; children in developing countries

Polymicrobial infection More likely with direct inoculation (eg, penetrating trauma) or contiguous spread (eg, from skull, face, hands, feet)

MRSA: methicillin-resistant S. aureus; CGD: chronic granulomatous disease; Hib: H. influenzae type b.

Graphic 96510 Version 8.0

Imaging abnormalities in osteomyelitis

Imaging Abnormal findings modality

Plain radiograph* Deep soft tissue swelling (3 days after onset)

Periosteal reaction or elevation (10 to 21 days after onset)

Lytic sclerosis (≥1 month after onset)

Magnetic resonance Bone marrow inflammation (decreased signal in T1-weighted images; increased signal in T2- imaging weighted images)

Edema in marrow and soft tissues

Penumbra sign (high-intensity-signal transition zone between abscess and sclerotic bone marrow in T1-weighted images)

With gadolinium enhancement: absent blood flow, suggestive of necrosis or abscess

Three-phase bone Focal uptake of tracer in the third phase (delayed phase) scan

Computed Increased density of bone marrow tomography Cortex destruction

Periosteal reaction (new bone formation) formation

Periosteal purulence

Sequestra (devitalized, sclerotic bone)

Ultrasonography Fluid collection adjacent to bone without intervening soft tissue

Thickening of periosteum

Periosteal elevation

* The timing and typical sequence of radiographic changes may vary with the site of infection and age of the patient.

Graphic 96767 Version 3.0

Comparison of imaging modalities in children with osteomyelitis

Modality Indications Advantages Disadvantages Comments*

Planning surgical pyomyositis intervention

MRI: magnetic resonance imaging; CT: computed tomography. * Values for sensitivity and specificity are from: Dartnell J, Ramachandran M, Katchburian M. Haematogenous acute and

Graphic 96521 Version 4.0

Early osteomyelitis in a six-year-old with fever and ankle pain

Courtesy of Marvin B Harper, MD.

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Osteomyelitis with subperiosteal abscess

Radiograph of the femur demonstrates periosteal elevation due to a subperiosteal abscess as the result of osteomyelitis.

Courtesy of Marvin B Harper, MD.

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Lytic lucency in osteomyelitis

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Penumbra sign in osteomyelitis

Magnetic resonance imaging (MRI) scan shows the penumbra sign (a transitional zone with relatively high signal intensity between abscess and sclerotic bone marrow on T1-weighted MRI).

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Acute osteomyelitis

Courtesy of Jon Mader, MD.

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Early repair in acute osteomyelitis

Courtesy of Jon Mader, MD.

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Chronic osteomyelitis

Courtesy of Jon Mader, MD.

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Magnetic resonance image of left hip effusion

(A) Axial and (B) coronal image of left hip effusion. The bright collection seen around the femoral neck (arrows) is a left hip effusion. The images were obtained using a fast spin echo-inversion recovery (FSE-IR) sequence, which is fluid sensitive.

Courtesy of Michael Rosenthal, MD, PhD.

Graphic 69485 Version 4.0

Right femoral osteomyelitis complicated by femoral shortening

Standing teleogram 18 months after right femoral osteomyelitis involving most of the right femur, which was complicated by femoral shortening.

Courtesy of William A Phillips, MD.

Graphic 120547 Version 1.0

Left femoral osteomyelitis complicated by femoral overgrowth

Standing teleogram 2 years, 3 months after left femoral osteomyelitis, which was complicated by left femoral overgrowth resulting in marked pelvic tilt (solid line).

Courtesy of William A Phillips, MD.

Graphic 120546 Version 2.0

Pulmonary septic emboli in community-associated methicillin-resistant Staphylococcus aureus (CA-MRSA) osteomyelitis

Computed tomography of the chest in a nine-year-old with CA-MRSA osteomyelitis of the tibia demonstrating multiple nodules consistent with pulmonary emboli.

Courtesy of Sheldon L Kaplan, MD. Texas Children's Hospital.

Graphic 58955 Version 3.0

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https://www.uptodate.com/...rint?search=osteomyelitis&source=search_result&selectedTitle=9~150&usage_type=default&display_rank=9[19.03.2020 15:33:08] Osteomyelitis in adults: Clinical manifestations and diagnosis - UpToDate

Official reprint from UpToDate® www.uptodate.com ©2020 UpToDate, Inc. and/or its affiliates. All Rights Reserved. Print Options Print | Back Text References Graphics Osteomyelitis in adults: Clinical manifestations and diagnosisContributor Disclosures Authors: Tahaniyat Lalani, MBBS, MHS, Steven K Schmitt, MD, FIDSA Section Editor: Denis Spelman, MBBS, FRACP, FRCPA, MPH Deputy Editor: Elinor L Baron, MD, DTMH

All topics are updated as new evidence becomes available and our peer review process is complete.

Literature review current through: Feb 2020. | This topic last updated: Mar 28, 2019.

INTRODUCTION

Osteomyelitis is an infection involving bone. Osteomyelitis may be classified based on the mechanism of infection (hematogenous versus nonhematogenous) and the duration of illness (acute versus chronic) [1].

Issues related to the classification, epidemiology, microbiology, clinical manifestations, and diagnosis of osteomyelitis in adults are presented here. Issues related to treatment of osteomyelitis are discussed separately. (See "Osteomyelitis in adults: Treatment".)

Issues related to vertebral osteomyelitis, pelvic and sacral osteomyelitis, and osteomyelitis in the setting of trauma are discussed in detail separately. (See "Vertebral osteomyelitis and discitis in adults" and "Pelvic osteomyelitis and other infections of the bony pelvis in adults" and "Osteomyelitis associated with open fractures in adults".)

Issues related to prosthetic joint infections are discussed separately. (See "Prosthetic joint infection: Epidemiology, microbiology, clinical manifestations, and diagnosis".)

Issues related to osteomyelitis in children are discussed separately. (See "Hematogenous osteomyelitis in children: Evaluation and diagnosis" and "Hematogenous osteomyelitis in children: Management".)

CLASSIFICATION

Osteomyelitis may be classified based on the duration of illness (acute versus chronic) and the mechanism of infection (hematogenous versus nonhematogenous). This approach to classification was described by Lew and Waldvogel [2-4].

Acute osteomyelitis typically presents with a symptom duration of a few days or weeks. Sequestra (pieces of necrotic bone that separate from viable bone) are absent.

https://www.uptodate.com/...rint?search=osteomyelitis&source=search_result&selectedTitle=2~150&usage_type=default&display_rank=2[19.03.2020 15:29:58] Osteomyelitis in adults: Clinical manifestations and diagnosis - UpToDate

Chronic osteomyelitis is characterized by long-standing infection over months or years. Sequestra are usually present; they form as a result of bone ischemia and necrosis in the context of blood vessel compression due to elevated medullary pressure associated with bone marrow inflammation. Sequestra can be seen radiographically. The presence of a sinus tract is pathognomonic of chronic osteomyelitis. (See "Approach to imaging modalities in the setting of suspected nonvertebral osteomyelitis".)

Nonhematogenous osteomyelitis can occur as a result of contiguous spread of infection to bone from adjacent soft tissues and joints or via direct inoculation of infection into the bone (as a result of trauma or surgery).

Hematogenous osteomyelitis is caused by microorganisms that seed the bone in the setting of bacteremia.

NONHEMATOGENOUS OSTEOMYELITIS

Epidemiology — Among younger adults, nonhematogenous osteomyelitis occurs most commonly in the setting of trauma and related surgery. Among older adults, nonhematogenous osteomyelitis occurs most commonly as a result of contiguous spread of infection to bone from adjacent soft tissues and joints (such as in the setting of diabetic foot wounds or decubitus ulcers) [2].

Risk factors for nonhematogenous osteomyelitis include poorly healing soft tissue wounds (including decubitus ulcers), presence of orthopedic hardware, diabetes, peripheral vascular disease, and peripheral neuropathy.

Microbiology — Nonhematogenous osteomyelitis may be polymicrobial or monomicrobial. Staphylococcus aureus (including methicillin-resistant S. aureus), coagulase-negative staphylococci, and aerobic gram-negative bacilli are the most common organisms. In one study, staphylococci were isolated in 53 percent of bone biopsy specimens, enterococci in 8 percent, streptococci in 12 percent, and anaerobes in 5 percent [5].

Other pathogens including corynebacteria, fungi, and mycobacteria have also been implicated [4-8].

Clinical manifestations

Signs and symptoms — Acute osteomyelitis typically presents with gradual onset of symptoms over several days. Patients usually present with dull pain at the involved site, with or without movement. Local findings (tenderness, warmth, erythema, and swelling) and systemic symptoms (fever, rigors) may also be present. Patients with osteomyelitis involving the hip, vertebrae, or pelvis tend to manifest few signs or symptoms other than pain.

Chronic osteomyelitis may manifest as pain, erythema, or swelling, sometimes in association with a draining sinus tract; fever is usually absent. Chronic osteomyelitis may also present with intermittent flares of pain and swelling. The presence of a sinus tract is pathognomonic of chronic osteomyelitis.

The diagnosis of chronic osteomyelitis can be particularly challenging when prosthetic material, extensive skin or soft tissue ulceration, or ischemic changes due to vascular insufficiency are also present [9]. Deep or extensive ulcers that fail to heal after several weeks of appropriate ulcer care should raise suspicion for chronic osteomyelitis, particularly when such lesions overlie bony prominences [9,10]. Chronic osteomyelitis may also present as a nonhealing fractures.

Patients with diabetes and chronic osteomyelitis may present with atypical findings. Diabetics who develop cutaneous ulcers often develop osteomyelitis before exposed bone is present on exam [9]. If a diabetic foot ulcer is larger than 2 cm2 or if exposed bone is present, osteomyelitis is highly likely [9,11]. (See "Clinical manifestations, diagnosis, and management of diabetic infections of the lower extremities".)

Osteomyelitis of the foot may develop following nail puncture through a shoe; Pseudomonas aeruginosa is a typical pathogen in such cases. (See "Infectious complications of puncture wounds" and "Pseudomonas aeruginosa skin and soft tissue infections", section on 'Infection following nail puncture'.)

Probing to bone — Probing to bone with a sterile blunt metal tool should be included in the initial assessment of diabetic patients with infected pedal ulcers. A positive result consists of detection of a hard, gritty surface [10-12]. The reliability of the probe-to-bone test may vary by the ulcer location and the expertise of the clinician performing the test [13,14].

The performance characteristics of the test have been evaluated in the setting of diabetic foot ulcers. In practice, the test is also used for evaluating nondiabetic ulcers due to peripheral neuropathy, vasculopathy, or pressure sores, although the performance characteristics have not been evaluated in these settings.

In a systematic review evaluating the performance of the probe-to-bone test (using bone histopathology or culture as the reference standard), the pooled sensitivity and specificity for the test were 87 and 83 percent, respectively [15]. An important limitation was the potential for selection and verification bias; the studies included in the analysis did not specify whether the results of the probe-to-bone test influenced pursuit of bone biopsy or culture nor whether interpreters of the reference standard were blinded to results of the probe-to-bone test.

The probe-to-bone test should be used as a screening tool in conjunction with the patient's pretest probability for osteomyelitis to determine whether additional tests (such as radiographic imaging or bone biopsy) are needed for diagnosis of diabetic foot osteomyelitis [16].

Laboratory tests — Laboratory findings are nonspecific. In the setting of acute osteomyelitis, leukocytosis and elevated serum inflammatory markers (erythrocyte sedimentation rate [ESR] and/or C-

reactive protein [CRP]) may be observed [17]. In the setting of chronic osteomyelitis, leukocytosis is uncommon; the ESR and/or CRP may be elevated or normal [18,19].

HEMATOGENOUS OSTEOMYELITIS

Hematogenous osteomyelitis is caused by microorganisms that seed the bone in the setting of bacteremia.

Epidemiology — Hematogenous osteomyelitis occurs most commonly in children [20]. (See "Hematogenous osteomyelitis in children: Epidemiology, pathogenesis, and microbiology".)

Vertebral osteomyelitis is the most common form of hematogenous osteomyelitis in adults. Issues related to vertebral osteomyelitis are discussed separately. (See "Vertebral osteomyelitis and discitis in adults".)

Among adults, hematogenous osteomyelitis accounts more frequently in males. Most cases occur in patients >50 years [21], except for injection drug users, most of whom are <40 years of age [22].

Risk factors for hematogenous osteomyelitis include endocarditis, presence of indwelling intravascular devices (eg, vascular catheters, cardiovascular devices) or orthopedic hardware, injection drug use, hemodialysis, and sickle cell disease [23].

Microbiology — Hematogenous osteomyelitis occurs following bacteremia. Patients may present following clearance of bacteremia, so blood cultures are not always positive.

Hematogenous osteomyelitis is usually monomicrobial; S. aureus is by far the most commonly isolated organism. In some cases, hematogenous osteomyelitis due to S. aureus presents with multifocal involvement [2,24-26]. Aerobic gram-negative rods are identified in up to 30 percent of cases.

Among injection drug users, hematogenous osteomyelitis due to P. aeruginosa and Serratia marcescens has been described [27]. Among immunosuppressed patients, hematogenous osteomyelitis due to Aspergillus spp has been described [28].

Hematogenous osteomyelitis due to beta-hemolytic streptococci is relatively rare (<1 percent of cases) [29]. Other less common pathogens include Mycobacterium tuberculosis [30], Candida spp [31-33], Bartonella henselae [34], Coccidioides immitis [35,36], and Cutibacterium (formerly Propionibacterium) acnes [37].

Clinical manifestations

Signs and symptoms — In general, signs and symptoms of hematogenous osteomyelitis may be indistinguishable from those of nonhematogenous osteomyelitis, discussed above. (See 'Signs and symptoms' above.)

Signs and symptoms referable to specific forms of hematogenous osteomyelitis are discussed in the following sections. https://www.uptodate.com/...rint?search=osteomyelitis&source=search_result&selectedTitle=2~150&usage_type=default&display_rank=2[19.03.2020 15:29:58] Osteomyelitis in adults: Clinical manifestations and diagnosis - UpToDate

Forms of disease — Clinical manifestations of hematogenous osteomyelitis mirror those of nonhematogenous osteomyelitis. (See 'Clinical manifestations' above.)

Clinical presentations that are unique to hematogenous osteomyelitis are discussed in the following sections. In some cases, adults with hematogenous osteomyelitis may have no local symptoms referable to bones; soft tissue findings may be more prominent.

● Vertebral osteomyelitis – Vertebral osteomyelitis is the most common form of hematogenous osteomyelitis in adults. Issues related to vertebral osteomyelitis are discussed separately. (See "Vertebral osteomyelitis and discitis in adults".)

● Sternoclavicular and pelvic osteomyelitis – After vertebral osteomyelitis, next most common sites of hematogenous osteomyelitis in adults are the flat bones of the axial skeleton (such as the sternoclavicular and pelvic bones). These sites are involved most frequently among injection drug users; multifocal involvement may be observed in these patients [38-40].

Specific signs and symptoms of sternoclavicular osteomyelitis include anterior chest wall swelling, pain, and tenderness. Sternoclavicular osteomyelitis may present as a mass that is mistaken for a soft tissue abscess or atypical cellulitis. It can also present as infection of the manubriosternal symphysis (a fibrocartilage union of the manubrium and the body of the sternum). In addition, sternoclavicular osteomyelitis can develop as a complication of mediastinitis. Local symptoms include pain, swelling, erythema, and tenderness over the sternoclavicular joint, and infection can extend into the surrounding soft tissue including the pectoralis major. (See "Postoperative mediastinitis after cardiac surgery".)

Issues related to pelvic osteomyelitis are described separately. (See "Pelvic osteomyelitis and other infections of the bony pelvis in adults".)

● Long-bone osteomyelitis – The least common sites of hematogenous osteomyelitis in adults are the long bones of the appendicular skeleton (in contrast, this is the most common site of hematogenous osteomyelitis in children) [41]. The clinical presentation is variable; some present subacutely with low-grade fever and vague pain at the site of infection, while others present acutely with high fever, sharp pain, and swelling over the involved site. Long-bone osteomyelitis may be classified based on the degree of bone involvement as well as host factors (table 1) [42]. (See "Hematogenous osteomyelitis in children: Clinical features and complications".)

Long-bone osteomyelitis can also present as septic arthritis of the knee, hip, or shoulder. This occurs if infection within the metaphysis (the most common site of infection in long-bone osteomyelitis) breaks through the bone cortex, leading to discharge of pus into the joint. The clinical manifestations, diagnosis, and management of septic arthritis are described separately. (See "Septic arthritis in adults".)

• Brodie abscess – A Brodie abscess consists of a region of suppuration and necrosis https://www.uptodate.com/...rint?search=osteomyelitis&source=search_result&selectedTitle=2~150&usage_type=default&display_rank=2[19.03.2020 15:29:58] Osteomyelitis in adults: Clinical manifestations and diagnosis - UpToDate

encapsulated by granulation tissue within a rim of sclerotic bone. Brodie abscess occurs in the setting of subacute or chronic osteomyelitis in the metaphysis of long bones, typically in patients <25 years of age [43]. It is usually of hematogenous origin but can also occur in the setting of trauma.

The most common pathogen is S. aureus; other gram-positive and gram-negative organisms (including P. aeruginosa, Klebsiella spp, and other gram-negative rods) may be seen. Cultures may be sterile in up to half of cases.

Patients with Brodie abscess typically present with insidious onset of mild to moderate pain lasting for several weeks to months, with or without fever. If the subacute process progresses to chronic localized bone abscess, patients present with longstanding dull pain in the absence of fever [44,45]. The most common site is the distal tibia; other sites include the femur, fibula, radius, and ulna [46].

Radiography typically demonstrates a single lesion near the metaphysis (image 1).

• Osteomyelitis in sickle cell disease – Osteomyelitis is a common complication of sickle cell disease; it occurs in more than 10 percent of patients [1]. This issue is discussed further separately. (See "Acute and chronic bone complications of sickle cell disease", section on 'Osteomyelitis and septic arthritis'.)

● Emphysematous osteomyelitis - Emphysematous osteomyelitis is a rare form of osteomyelitis characterized by intraosseous gas in the extra-axial skeleton (eg, pelvis, sacrum, lower extremity bones) or vertebrae [47-49]. It can occur via hematogenous spread or via contiguous spread from an intra-abdominal source, is usually associated with underlying comorbidities (eg, diabetes or malignancy), and may be monomicrobial or polymicrobial. The most commonly associated organisms include Enterobacteriaceae and Fusobacterium necrophorum.

COMPLICATIONS

Complications of osteomyelitis include:

● Sinus tract formation ● Contiguous soft tissue infection ● Abscess ● Septic arthritis ● Systemic infection ● Bony deformity ● Fracture [50] ● Malignancy [51-58]

DIAGNOSIS

Overview — A clinical presentation of osteomyelitis should be suspected in the following circumstances:

● Nonhematogenous osteomyelitis should be suspected in the setting of new or worsening musculoskeletal pain, particularly in patients with poorly healing soft tissue or surgical wounds adjacent to bony structures, in patients with signs of cellulitis overlying previously implanted orthopedic hardware, and in patients with traumatic injury (including bite and puncture wounds). It should also be suspected in diabetic patients with ulcers that probe to bone.

● Hematogenous osteomyelitis should be suspected in the setting of new or worsening musculoskeletal pain, particularly in the setting of fever and/or recent bacteremia.

In general, the diagnosis of osteomyelitis is established via culture obtained from biopsy of the involved bone [10].

A diagnosis of osteomyelitis may be inferred in the following circumstances:

● Clinical and radiographic findings typical of osteomyelitis and positive blood cultures with a likely pathogen (such as S. aureus); in such cases, bone biopsy is not required but may be useful, particularly if subsequent therapeutic debridement is needed.

● Bone histopathology consistent with osteomyelitis in the absence of positive culture data (particularly in the setting of recent antibiotic administration).

● Suggestive clinical and typical radiographic findings and persistently elevated inflammatory markers in circumstances with no positive culture data and a biopsy is not feasible.

Issues related to diagnosis of vertebral osteomyelitis are discussed separately. (See "Vertebral osteomyelitis and discitis in adults".)

Clinical approach — Initial evaluation of patients with suspected osteomyelitis includes history and physical examination; predisposing factors or events should be elicited (such as underlying diabetes, vasculopathy, invasive procedures, or injection drug use). (See 'Epidemiology' above and 'Epidemiology' above.)

If osteomyelitis is suspected based on clinical history and physical findings, laboratory evaluation (including erythrocyte sedimentation rate [ESR], C-reactive protein [CRP], white blood cell count), blood cultures, and radiographic imaging should be obtained. ESR and CRP are sensitive but not specific for osteomyelitis; if elevated initially, they can be useful for treatment monitoring. (See "Osteomyelitis in adults: Treatment", section on 'Laboratory monitoring'.)

In patients with ≥2 weeks of symptoms, conventional radiography is a reasonable initial imaging modality for evaluation of suspected osteomyelitis. In patients with <2 weeks of symptoms, an advanced imaging modality should be pursued. Advanced imaging is also warranted for patients with diabetes, localized

symptoms, and/or abnormal laboratory results whose plain radiographs are normal or suggestive of osteomyelitis without characteristic features.

The optimal radiographic modality may depend upon specific clinical circumstances and should be tailored accordingly for individual patients, in discussion with radiologist expertise if necessary. The following concepts may help guide selection of radiographic modality (see "Approach to imaging modalities in the setting of suspected nonvertebral osteomyelitis"):

● If the patient is diabetic and has symptoms referable to the foot, magnetic resonance imaging (MRI) is the test of choice.

● If metal hardware precludes MRI or computed tomography (CT), a nuclear study is the test of choice. The limitations of nuclear studies are discussed separately and should be considered in interpretation of results.

Findings of osteomyelitis on radiographic imaging should prompt bone biopsy for culture and histology to confirm the diagnosis and to guide antimicrobial therapy, unless blood cultures are positive for a likely pathogen (such as S. aureus, a gram-negative enteric rod, or P. aeruginosa). Osteomyelitis is unlikely in the absence of radiographic evidence on MRI, CT, or nuclear imaging.

If blood cultures and needle aspirate cultures are negative and the clinical suspicion for osteomyelitis remains high on the basis of clinical and radiographic findings, repeat bone biopsy (either percutaneous or open) should be performed. If this specimen is also nondiagnostic, an empiric antimicrobial regimen should be initiated against common gram-positive and gram-negative bacterial pathogens. (See "Osteomyelitis in adults: Treatment".)

If there is evidence of soft tissue infection over a bony surface without radiographic evidence of osteomyelitis, an empiric course of therapy for soft tissue infection may be appropriate [10].

Blood cultures — Blood cultures are positive in about half of cases of acute osteomyelitis; their utility is highest in the setting of hematogenous infection [2,59,60]. The yield of blood cultures is likely greatest in the setting of associated fever and/or in the setting of suspected vertebral osteomyelitis or suspected concurrent infective endocarditis.

Positive blood cultures may obviate the need for invasive diagnostic testing if the organism isolated from blood is a pathogen likely to cause osteomyelitis.

Bone biopsy — Bone biopsy (open or percutaneous) should be obtained for pathogen identification and to obtain susceptibility data when this is feasible; biopsy is also useful if the diagnosis of osteomyelitis is uncertain [5,24,61-63]. Cultures of bone biopsy material yield positive findings in up to 87 percent of cases [62]. Cultures of swabs or material from needle puncture (eg, aspiration of material in the soft tissue rather than bone) should not be used to establish an osteomyelitis pathogen, since the correlation between bone biopsy culture and these specimens is poor, especially in cases of diabetic foot infections or decubitus ulcers [5,64].

Cessation of antibiotics 48 to 72 hours prior to bone biopsy may increase the microbiological yield, but often bone cultures are positive regardless of prior antibiotic therapy because such infections occur in areas of simultaneous infection-induced bony infarction or ischemia.

Open biopsy is preferable over needle biopsy. In circumstances where surgical debridement is required (such as decubitus ulcers or wounds with compromised vasculature), bone samples should be obtained at the time of surgical debridement [65].

Percutaneous needle biopsy is an alternative to open biopsy; this technique is less reliable than open biopsy given problems with sampling error. This was illustrated in a study including 31 diabetic patients in which culture results from needle biopsies were compared with open biopsies; needle biopsy had a lower yield than open biopsy, and the correlation between culture results obtained by needle biopsy and open biopsy was only 23 percent [64]. In addition, the sensitivity of needle biopsy can be particularly low in postoperative or post-traumatic settings [62,66]. If the clinical suspicion for osteomyelitis is high in the setting of negative cultures from blood and needle biopsy, the needle biopsy should be repeated or an open biopsy performed.

Percutaneous procedures should be performed through intact tissues (rather than inflamed or ulcerated skin) to obtain accurate culture results. Fluoroscopic or CT guidance for percutaneous procedures is preferable. Ideally, the biopsy should be obtained prior to treatment with antimicrobial therapy. At least two specimens should be obtained so that one can be sent for Gram stain and culture (including aerobic anaerobic, mycobacterial, and fungal studies) and the other for histopathology.

Bone biopsy may not be needed for patients with radiographic studies consistent with osteomyelitis in the setting of positive blood cultures or when prior bone cultures have been obtained in a patient with clear evidence for relapse of prior bone infection. In addition, it may be impractical to obtain a bone biopsy in some circumstances since the biopsy site may heal poorly in the setting of advanced vascular disease. In such cases, empiric management should be pursued. (See "Osteomyelitis in adults: Treatment".)

Cultures — The identification of the causative pathogen(s) is crucial and is best accomplished by bone biopsy (obtained surgically or by radiographically guided intervention). At least two specimens should be obtained so that one can be sent for Gram stain and culture (including aerobic, anaerobic, mycobacterial, and fungal cultures) and the other can be sent for histopathology [67].

Sinus tract cultures may be of some use for prediction of osteomyelitis if S. aureus or Salmonella spp are identified; however, in general, such cultures are not worthwhile because the results do not correlate reliably with the pathogen in the underlying bone [5,66,68-70]. In one report of 40 patients with chronic osteomyelitis, only 44 percent of sinus tract cultures contained the pathogen isolated from a deep surgical specimen [70]. Isolation of S. aureus from the sinus tract culture had some predictive value, although the absence of S. aureus in the sinus tract did not preclude its presence on bone biopsy. Culturing other organisms is not predictive for those that will be found on bone biopsy [70].

Sonication of explanted hardware may be useful to detect microorganisms that are highly adherent to https://www.uptodate.com/...rint?search=osteomyelitis&source=search_result&selectedTitle=2~150&usage_type=default&display_rank=2[19.03.2020 15:29:58] Osteomyelitis in adults: Clinical manifestations and diagnosis - UpToDate

fixation hardware, although this procedure is not routinely available in most microbiology laboratories [17,71,72].

Histopathology — Histopathologic features of osteomyelitis include necrotic bone with extensive resorption adjacent to an inflammatory exudate [73]. Stains for bacteria, mycobacteria, and fungi should be on histopathology specimens. Histopathology is discussed further separately. (See "Pathogenesis of osteomyelitis".)

Radiography — The general role of radiographic studies in the diagnosis of osteomyelitis is discussed above. (See 'Clinical approach' above.)

A more detailed discussion of radiographic modalities in the setting of suspected osteomyelitis is discussed separately. (See "Approach to imaging modalities in the setting of suspected nonvertebral osteomyelitis".)

DIFFERENTIAL DIAGNOSIS

The differential diagnosis of osteomyelitis includes:

● Soft tissue infection – Soft tissue infection may occur alone or in conjunction with osteomyelitis. In general, it is prudent to pursue imaging for assessment of bone involvement in the setting of chronic soft tissue infection that fails to improve with appropriate antibiotic therapy; this occurs more often in the setting of diabetes. (See "Clinical manifestations, diagnosis, and management of diabetic infections of the lower extremities".)

● Charcot arthropathy – Acute Charcot neuroarthropathy may present with localized erythema and warmth; it can be difficult to determine if such patients have Charcot arthropathy or osteomyelitis (or both). Furthermore, patients with Charcot arthropathy commonly develop skin ulcerations that can in turn lead to secondary osteomyelitis. Magnetic resonance imaging (MRI; contrast-enhanced) may be diagnostically useful if it shows a sinus tract, replacement of soft tissue fat, a fluid collection, or extensive marrow abnormalities. Bone biopsy may be needed for definitive diagnosis. (See "Diabetic neuropathic arthropathy".)

● Osteonecrosis – Osteonecrosis (avascular necrosis of bone) is usually relatively easy to distinguish from osteomyelitis since a precipitating cause is usually present (such as steroids, radiation, or bisphosphonate use). Associated osteomyelitis may occur in patients with mandibular osteonecrosis. (See "Risks of therapy with bone antiresorptive agents in patients with advanced malignancy", section on 'Osteonecrosis of the jaw' and "Osteonecrosis (avascular necrosis of bone)".)

● Gout – Both osteomyelitis and gout can present with joint inflammation; the presentation of gout is usually more acute than the presentation of osteomyelitis. Gout is distinguished by presence of uric acid crystals in joint fluid. (See "Clinical manifestations and diagnosis of gout".)

● Fracture – Osteomyelitis may mimic the appearance of fracture on radiographic imaging; fracture is typically associated with antecedent trauma. In some cases, bone biopsy may be required to distinguish these two entities, particularly in the absence of healing following suspected fracture. (See "General principles of fracture management: Early and late complications".)

● Bursitis – Both osteomyelitis and bursitis can present with inflammation of the bursa; osteomyelitis involves infection of the underlying bone whereas bursitis involves infection that is confined to the bursa. The two are distinguished by clinical history, physical examination, radiography, and bursa aspiration. (See "Septic bursitis".)

● Bone tumor – Both osteomyelitis and bone tumor may present with bone pain [74,75]; bone tumor is generally distinguished by radiographic imaging and bone biopsy. (See "Bone tumors: Diagnosis and biopsy techniques".)

● Sickle cell vaso-occlusive pain crisis – In patients with sickle cell disease, the clinical presentation of osteomyelitis may be difficult to distinguish from a vaso-occlusive pain crisis. Osteomyelitis is more likely to be associated with a prolonged duration of fever and pain localized to a single site. (See "Acute and chronic bone complications of sickle cell disease", section on 'Osteomyelitis and septic arthritis'.)

● Synovitis, acne, pustulosis, hyperostosis, and osteitis (SAPHO) – SAPHO syndrome consists of a wide spectrum of neutrophilic dermatoses associated with aseptic osteoarticular lesions. It can mimic osteomyelitis in patients who lack the characteristic findings of pustulosis and synovitis. The diagnosis is established via clinical manifestations; bone culture is sterile in the setting of osteitis. (See "SAPHO (synovitis, acne, pustulosis, hyperostosis, osteitis) syndrome" and "Major causes of musculoskeletal chest pain in adults", section on 'Sternocostoclavicular hyperostosis (SAPHO syndrome)'.)

● Complex regional pain syndrome (CRPS) – CRPS is characterized by pain, swelling, limited range of motion, skin changes, and patchy bone demineralization, usually of the distal limbs. It frequently begins following a fracture, soft tissue injury, or surgery. Patients with osteomyelitis lack symptoms of vasomotor instability observed with CRPS. Radiographic evaluation with MRI can differentiate between osteomyelitis and CRPS. (See "Complex regional pain syndrome in adults: Pathogenesis, clinical manifestations, and diagnosis".)

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● Basics topic (see "Patient education: Osteomyelitis in adults (The Basics)")

SUMMARY

● Osteomyelitis is an infection involving bone. Osteomyelitis may be classified based on the mechanism of infection (hematogenous versus nonhematogenous) and the duration of illness (acute versus chronic). Nonhematogenous osteomyelitis can occur as a result of contiguous spread of infection to bone from adjacent soft tissues and joints or via direct inoculation of infection into the bone (as a result of trauma, bite wounds, or surgery). Hematogenous osteomyelitis is caused by microorganisms that seed the bone in the setting of bacteremia. (See 'Classification' above.)

● Hematogenous osteomyelitis should be suspected in the setting of new or worsening musculoskeletal pain, particularly in the setting of fever and/or recent bacteremia. Vertebral osteomyelitis is the most common form of hematogenous osteomyelitis in adults. Issues related to vertebral osteomyelitis are discussed separately. (See 'Overview' above and "Vertebral osteomyelitis and discitis in adults".)

● In general, the diagnosis of osteomyelitis is established via culture obtained from biopsy of the involved bone. A diagnosis of osteomyelitis may be inferred in the following circumstances (see 'Overview' above):

• Clinical and radiographic findings typical of osteomyelitis and positive blood cultures with a likely

pathogen (such as Staphylococcus aureus); in such cases, bone biopsy is not required but may be useful, particularly if subsequent therapeutic debridement is needed.

• Bone histopathology consistent with osteomyelitis in the absence of positive culture data (particularly in the setting of recent antibiotic administration).

• Suggestive clinical and typical radiographic findings and persistently elevated inflammatory markers, in circumstances with no positive culture data and a biopsy is not feasible.

● Patients with suspected osteomyelitis should undergo laboratory evaluation (including erythrocyte sedimentation rate, C-reactive protein, white blood cell count), blood cultures, and radiographic imaging. In patients with ≥2 weeks of symptoms, conventional radiography is a reasonable initial imaging modality. In patients with <2 weeks of symptoms, an advanced imaging modality (magnetic resonance imaging, computed tomography, or nuclear imaging) should be pursued. Advanced imaging is also warranted for patients with diabetes, localized symptoms, and/or abnormal laboratory results whose plain radiographs are normal or suggestive of osteomyelitis without characteristic features. Osteomyelitis is unlikely in the absence of radiographic evidence on advanced imaging. (See 'Clinical approach' above.)

● Findings of osteomyelitis on radiographic imaging should prompt bone biopsy for culture and histology to confirm the diagnosis and to guide antimicrobial therapy, unless blood cultures are positive for a likely pathogen (such as S. aureus, a gram-negative enteric rod, or Pseudomonas aeruginosa). (See 'Clinical approach' above.)

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37. Do TT, Strub WM, Witte D. Subacute Propionibacterium acnes osteomyelitis of the spine in an adolescent. J Pediatr Orthop B 2003; 12:284.

38. Gordon RJ, Lowy FD. Bacterial infections in drug users. N Engl J Med 2005; 353:1945.

39. Dajer-Fadel WL, Ibarra-Pérez C, Borrego-Borrego R, et al. Descending necrotizing mediastinitis and sternoclavicular joint osteomyelitis. Asian Cardiovasc Thorac Ann 2013; 21:618.

40. Vu TT, Yammine NV, Al-Hakami H, et al. Sternoclavicular joint osteomyelitis following head and neck surgery. Laryngoscope 2010; 120:920.

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42. Cierny G 3rd, Mader JT, Penninck JJ. A clinical staging system for adult osteomyelitis. Clin Orthop Relat Res 2003; :7.

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50. Gelfand MS, Cleveland KO, Heck RK, Goswami R. Pathological fracture in acute osteomyelitis of long bones secondary to community-acquired methicillin-resistant Staphylococcus aureus: two

cases and review of the literature. Am J Med Sci 2006; 332:357.

51. Altay M, Arikan M, Yildiz Y, Saglik Y. Squamous cell carcinoma arising in chronic osteomyelitis in foot and ankle. Foot Ankle Int 2004; 25:805.

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53. Bacchini P, Calderoni P, Gherlinzoni F, Gualtieri G. Angiosarcoma in chronic osteomyelitis. Ital J Orthop Traumatol 1984; 10:393.

54. Campanacci M. Carcinomas and sarcomas on chronic osteomyelitis. In: Bone and Soft Tissue Tum ors, Springer-Verlag Wien, 1990. p.661.

55. Czerwiński E, Skolarczyk A, Frasik W. Malignant fibrous histiocytoma in the course of chronic osteomyelitis. Arch Orthop Trauma Surg 1991; 111:58.

56. Johnston RM, Miles JS. Sarcomas arising from chronic osteomyelitic sinuses. A report of two cases. J Bone Joint Surg Am 1973; 55:162.

57. Kennedy C, Stoker DJ. Malignant fibrous histiocytoma complicating chronic osteomyelitis. Clin Radiol 1990; 41:435.

58. McGrory JE, Pritchard DJ, Unni KK, et al. Malignant lesions arising in chronic osteomyelitis. Clin Orthop Relat Res 1999; :181.

59. Nolla JM, Ariza J, Gómez-Vaquero C, et al. Spontaneous pyogenic vertebral osteomyelitis in nondrug users. Semin Arthritis Rheum 2002; 31:271.

60. Patzakis MJ, Rao S, Wilkins J, et al. Analysis of 61 cases of vertebral osteomyelitis. Clin Orthop Relat Res 1991; :178.

61. White LM, Schweitzer ME, Deely DM, Gannon F. Study of osteomyelitis: utility of combined histologic and microbiologic evaluation of percutaneous biopsy samples. Radiology 1995; 197:840.

62. Howard CB, Einhorn M, Dagan R, et al. Fine-needle bone biopsy to diagnose osteomyelitis. J Bone Joint Surg Br 1994; 76:311.

63. Wheat J. Diagnostic strategies in osteomyelitis. Am J Med 1985; 78:218.

64. Senneville E, Morant H, Descamps D, et al. Needle puncture and transcutaneous bone biopsy cultures are inconsistent in patients with diabetes and suspected osteomyelitis of the foot. Clin Infect Dis 2009; 48:888.

65. Darouiche RO, Landon GC, Klima M, et al. Osteomyelitis associated with pressure sores. Arch Intern Med 1994; 154:753. https://www.uptodate.com/...rint?search=osteomyelitis&source=search_result&selectedTitle=2~150&usage_type=default&display_rank=2[19.03.2020 15:29:58] Osteomyelitis in adults: Clinical manifestations and diagnosis - UpToDate

66. Perry CR, Pearson RL, Miller GA. Accuracy of cultures of material from swabbing of the superficial aspect of the wound and needle biopsy in the preoperative assessment of osteomyelitis. J Bone Joint Surg Am 1991; 73:745.

67. Gross T, Kaim AH, Regazzoni P, Widmer AF. Current concepts in posttraumatic osteomyelitis: a diagnostic challenge with new imaging options. J Trauma 2002; 52:1210.

68. Khatri G, Wagner DK, Sohnle PG. Effect of bone biopsy in guiding antimicrobial therapy for osteomyelitis complicating open wounds. Am J Med Sci 2001; 321:367.

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71. Trampuz A, Piper KE, Hanssen AD, et al. Sonication of explanted prosthetic components in bags for diagnosis of prosthetic joint infection is associated with risk of contamination. J Clin Microbiol 2006; 44:628.

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75. Seybold U, Talati NJ, Kizilbash Q, et al. Hematogenous osteomyelitis mimicking osteosarcoma due to Community Associated Methicillin-Resistant Staphylococcus aureus. Infection 2007; 35:190.

Topic 7668 Version 30.0

GRAPHICS

Cierny-Mader staging system for long-bone osteomyelitis

Anatomic type

Stage 1: Medullary osteomyelitis Medullary osteomyelitis denotes infection confined to the intramedullary surfaces of the bone. Hematogenous osteomyelitis and infected intramedullary rods are examples of this anatomic type.

Stage 2: Superficial osteomyelitis Superficial osteomyelitis is a true contiguous focus infection of bone; it occurs when an exposed infected necrotic surface of bone lies at the base of a soft-tissue wound.

Stage 3: Localized osteomyelitis Localized osteomyelitis is usually characterized by a full thickness, cortical sequestration, which can be removed surgically without compromising bony stability.

Stage 4: Diffuse osteomyelitis Diffuse osteomyelitis is a through-and-through process that usually requires an intercalary resection of the bone to arrest the disease process. Diffuse osteomyelitis includes those infections with a loss of bony stability either before or after debridement surgery.

Physiologic class of host*

Class A denotes a normal host

Class B denotes a host with systemic compromise, local compromise, or both

Class C denotes a host for whom the morbidity of treatment is worse than that imposed by the disease itself

Factors affecting immune surveillance, metabolism, and local vascularity

Systemic factors Local factors

Malnutrition Chronic lymphedema

Renal or hepatic failure Venous stasis

Diabetes mellitus Major vessel compromise

Chronic hypoxia Arteritis

Immune disease Small vessel disease

Malignancy Extensive scarring

Extremes of age Radiation fibrosis

Immunosuppression or immune deficiency Neuropathy

Tobacco abuse (≥2 packs per day)

* Host factors are important for prognosticating containment of infection. A systemically and/or locally compromised host cannot isolate an infectious focus as well as a normal host, so treatment of osteomyelitis is more difficult in such patients.

Adapted from: Cierny G, Mader JT, Pennick JJ. A clinical staging system for adult osteomyelitis. Contemp Orthop 1985; 10:17.

Graphic 64015 Version 5.0

Brodie abscess radiograph

Graphic 87102 Version 5.0

Contributor Disclosures

Tahaniyat Lalani, MBBS, MHS Nothing to disclose Steven K Schmitt, MD, FIDSA Nothing to disclose Denis Spelman, MBBS, FRACP, FRCPA, MPH Nothing to disclose Elinor L Baron, MD, DTMH Nothing to disclose

Conflict of interest policy

Contributor Disclosures

Tahaniyat Lalani, MBBS, MHS Nothing to disclose Steven K Schmitt, MD, FIDSA Nothing to disclose Denis Spelman, MBBS, FRACP, FRCPA, MPH Nothing to disclose Elinor L Baron, MD, DTMH Nothing to disclose

Conflict of interest policy

https://www.uptodate.com/...rint?search=osteomyelitis&source=search_result&selectedTitle=2~150&usage_type=default&display_rank=2[19.03.2020 15:29:58] Osteomyelitis in adults: Treatment - UpToDate

Official reprint from UpToDate® www.uptodate.com ©2020 UpToDate, Inc. and/or its affiliates. All Rights Reserved. Print Options Print | Back Text References Graphics Osteomyelitis in adults: Treatment Contributor Disclosures Authors: Douglas R Osmon, MD, Aaron J Tande, MD Section Editor: Denis Spelman, MBBS, FRACP, FRCPA, MPH Deputy Editor: Elinor L Baron, MD, DTMH

All topics are updated as new evidence becomes available and our peer review process is complete.

Literature review current through: Feb 2020. | This topic last updated: May 10, 2019.

INTRODUCTION

Treatment of osteomyelitis includes consideration of issues related to debridement, management of infected foreign bodies (if present), antibiotic selection, and duration of therapy; these issues are discussed in the following sections.

General issues related to treatment of osteomyelitis are discussed here. Issues related to clinical manifestations and diagnosis of osteomyelitis are discussed separately. (See "Osteomyelitis in adults: Clinical manifestations and diagnosis".)

Issues related to treatment of vertebral osteomyelitis, osteomyelitis associated with trauma, pelvic and sacral osteomyelitis, and prosthetic joint infection are discussed in detail separately. (See "Vertebral osteomyelitis and discitis in adults" and "Osteomyelitis associated with open fractures in adults" and "Pelvic osteomyelitis and other infections of the bony pelvis in adults" and "Prosthetic joint infection: Treatment".)

Issues related to osteomyelitis in children are presented separately. (See "Hematogenous osteomyelitis in children: Evaluation and diagnosis" and "Hematogenous osteomyelitis in children: Management".)

CLINICAL APPROACH

Nonhematogenous osteomyelitis

Absence of orthopedic hardware — In general, management of osteomyelitis (in the absence of orthopedic hardware) consists of operative debridement followed by antimicrobial therapy for eradication of infection.

There may be a role for antimicrobial therapy alone (in the absence of surgical debridement) for carefully selected patients with diabetic foot osteomyelitis. In observational studies, success rates for treatment of

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diabetic foot osteomyelitis with antimicrobial therapy alone range from 64 to 82 percent [1-3]. In one small randomized trial including 37 patients treated with antibiotics alone for three months or surgical debridement and antibiotics for ten days, there was no difference in healing between the two groups [4]. However, patients with common comorbid conditions (such as arterial disease, Charcot arthropathy, and poorly controlled diabetes) were excluded.

Surgical debridement — Surgical debridement for management of osteomyelitis consists of removal of necrotic material and culture of involved tissue and bone. A satisfactory soft tissue envelope overlying the site of infection must be re-established for successful treatment, either via direct closure or flap coverage.

In the setting of dead or injured bone and/or infected fluid collections, surgical debridement (and revascularization, in some cases) is a cornerstone of therapy. Antimicrobial therapy alone is not effective for cure of infected, necrotic bone. In addition, antibiotic penetration into bone may be unreliable in patients with arterial insufficiency or prior scarring associated with trauma [5].

Surgical debridement also allows placement of local antimicrobials, either applied directly to the site of infection or mixed with absorbable (eg, calcium sulfate) or nonabsorbable (eg, polymethyl methacrylate cement) carriers. (See "Management of diabetic foot ulcers" and "Osteomyelitis associated with open fractures in adults".)

Patients who have received antibiotics recently and do not have an acute need for surgical intervention should discontinue antibiotics for at least two weeks prior to debridement to optimize microbiologic diagnosis. However, patients with necrotizing soft tissue infection or with systemic infection secondary to osteomyelitis in whom source control is needed should undergo early surgical debridement.

Antibiotic therapy — The clinical approach to antibiotic therapy is discussed in this section; issues related to selection of antibiotic therapy are discussed below. (See 'Antibiotic therapy' below.)

Residual infected bone present — Patients with residual infected bone that is not amenable to complete removal should be treated with a prolonged duration of intravenous or highly bioavailable oral antibiotic therapy, guided by antimicrobial susceptibility data (table 1). (See 'Antibiotic therapy' below.)

The optimal duration of antibiotic therapy for treatment of osteomyelitis with residual infected bone is uncertain. Most experts favor continuing antimicrobial therapy at least until debrided bone has been covered by vascularized soft tissue, which is usually at least six weeks from the last debridement [6]. Parenteral antimicrobial therapy can be administered on an outpatient basis via a peripherally inserted central catheter or similar device. In some circumstances, highly bioavailable oral antibiotic therapy may be administered.

While on parenteral antimicrobial therapy, patients should have weekly bloodwork for safety monitoring. (See 'Laboratory monitoring' below.)

No residual infected bone — Patients who undergo amputation or complete removal of all

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involved bone warrant a relatively short course of antibiotic therapy (table 1). In the absence of concomitant soft tissue infection, antibiotic therapy may be discontinued as early as two to five days after debridement. When there is evidence of soft tissue infection at the operative site, 10 to 14 days of pathogen-directed parenteral or highly bioavailable oral therapy is reasonable [5].

Presence of orthopedic hardware

Surgical debridement — In general, the approach to management of osteomyelitis associated with orthopedic hardware consists of operative debridement, obtaining bone biopsy for culture, and antimicrobial therapy tailored to culture and susceptibility data [7-9]. The need for hardware to maintain bone stability must be balanced with the potential impact of foreign material on propagation of infection. Additional factors influencing the approach include the microbiology of infection and individual patient circumstances.

Surgical management strategies include debridement with hardware retention or debridement with hardware removal. Hardware retention may be attempted when the stability of the bone and hardware construct would be compromised (such as in the case of fracture fixation hardware with unhealed fracture) or when there is a clear anatomic separation between the osteomyelitis and hardware. In contrast, hardware should be removed if the hardware is no longer needed for bone stability or if adequate debridement of the infected bone cannot be achieved with hardware retention.

Retained hardware — Patients with orthopedic hardware that is not amenable to removal and/or residual involved bone that is not amenable to complete debridement should be treated with a prolonged duration of intravenous antibiotic therapy (table 1). The optimal duration is uncertain; most experts favor six weeks of therapy. While on parenteral antimicrobial therapy, patients should have weekly bloodwork for safety monitoring. (See 'Laboratory monitoring' below.)

Following completion of parenteral therapy with resolution of clinical signs of acute infection, patients with retained hardware and/or necrotic bone not amenable to debridement should receive long-term antibiotic suppression with an oral agent, guided by antimicrobial susceptibility data. Regimens for antibiotic suppression are summarized in the table (table 2).

In general, oral antimicrobial suppression should be continued until fractures are united. Once fracture healing is demonstrated radiographically, the timeframe for discontinuation of oral antimicrobial suppression should be determined carefully. Factors influencing the duration of therapy include the microbiology of infection, the duration of infection prior to debridement, the tolerability of the antimicrobial suppression regimen, the status of the orthopedic hardware (if present) at the site of infection, and individual patient circumstances.

Patients who would be unable to tolerate additional surgery in the setting of relapse may warrant antimicrobial suppression for as long as the hardware remains in place. However, the benefit of https://www.uptodate.com/...rint?search=osteomyelitis&source=search_result&selectedTitle=1~150&usage_type=default&display_rank=1[19.03.2020 15:30:21] Osteomyelitis in adults: Treatment - UpToDate

continuing suppressive treatment for longer than six months is uncertain. In one observational study including 89 patients with retained orthopedic hardware, use of suppressive antibiotics for at least three months after diagnosis was associated with being free of clinical infection (odds ratio 3.5; 95% CI 1.3- 9.4), but use of suppressive antibiotic for at least six months after diagnosis was not [10].

Among patients who remain on antimicrobial suppression after fracture union, we discuss with the patient the benefits and adverse effects of ongoing suppression compared with discontinuing suppression. If hardware removal could be performed in the event of infection relapse (such as healed long-bone fracture), the infection appears to be well suppressed, and the patient is comfortable with the small possibility of further surgery, we offer discontinuation of suppression. If this small possibility of surgery is unacceptable, we continue suppression indefinitely.

No retained hardware — Patients with no retained hardware should complete a prolonged duration of intravenous antibiotic therapy (table 1). Most experts favor continuing antimicrobial therapy at least until debrided bone has been covered by vascularized soft tissue, which is usually at least six weeks from the last debridement.

While on parenteral antimicrobial therapy, patients should have weekly bloodwork for safety monitoring. (See 'Laboratory monitoring' below.)

Laboratory monitoring — Laboratory monitoring is needed during prolonged administration of antimicrobial therapy to monitor for adverse drug effects and to assess control of infection.

For patients on parenteral antimicrobial therapy, we obtain weekly complete blood count and chemistries. We obtain serum inflammatory markers (erythrocyte sedimentation rate and C-reactive protein) at the beginning and end of parenteral therapy and at the time of transition to oral suppressive therapy (if used).

We do not routinely monitor weekly serum inflammatory markers during parenteral antimicrobial therapy. However, if there is clinical suspicion for treatment failure, we use inflammatory markers (in conjunction with clinical examination and radiographic studies such as magnetic resonance imaging or plain radiograph) to guide further management. (See 'Persistently elevated inflammatory markers' below.)

For patients on oral suppressive antimicrobial therapy, we obtain a complete blood count, creatinine, and alanine aminotransferase at 2, 4, 8, and 12 weeks and then every 6 to 12 months thereafter.

Persistently elevated inflammatory markers — In the setting of persistently elevated inflammatory markers after completing a course of antibiotic therapy, the first priority should be to ensure that a thorough and complete debridement has been performed. In addition, the microbiologic diagnosis and susceptibility data should be reviewed.

Persistently elevated inflammatory markers two weeks following completion of antimicrobial therapy (without an alternative explanation) should prompt concern for persistent osteomyelitis [11,12]. Patients with associated symptoms warrant repeat debridement and additional antimicrobial therapy. In the absence of clinical signs consistent with persistent infection, clinical observation may be reasonable. https://www.uptodate.com/...rint?search=osteomyelitis&source=search_result&selectedTitle=1~150&usage_type=default&display_rank=1[19.03.2020 15:30:21] Osteomyelitis in adults: Treatment - UpToDate

Hematogenous (nonvertebral) osteomyelitis — In adults, hematogenous osteomyelitis most commonly involves the vertebral bones. Issues related to vertebral osteomyelitis are discussed separately. (See "Vertebral osteomyelitis and discitis in adults".)

Treatment of hematogenous (nonvertebral) osteomyelitis consists of parenteral antibiotics; in some circumstances, surgical debridement is also warranted.

In general, patients with infection confined to the medullary canal of the bone may be treated with antibiotics alone. Surgical debridement is warranted in patients with subperiosteal collection or abscess, necrotic bone, and/or in the setting of concomitant joint infection. Depending on the scope of the debridement, bone grafting or other orthopedic reconstruction may be required. A critical component of surgical management is adequate soft tissue coverage.

In all patients, blood cultures should be obtained prior to initiation of antibiotic therapy. If blood cultures are negative, a bone biopsy or aspirate of subperiosteal abscess for culture should be performed.

Empiric antibiotic coverage for treatment of hematogenous osteomyelitis should include activity against methicillin-resistant Staphylococcus aureus and aerobic gram-negative bacilli. An appropriate regimen consists of vancomycin and a third- or fourth-generation cephalosporin (table 1).

Once an etiologic organism is isolated, the antibiotic regimen should be tailored to susceptibility data [13].

The optimal duration of antibiotic therapy for treatment of hematogenous (nonvertebral) osteomyelitis is uncertain. In general, at least four weeks of parenteral therapy from the last major debridement (if performed) are warranted.

For patients on parenteral antimicrobial therapy, we obtain weekly complete blood count and chemistries. In addition, we obtain serum inflammatory markers (erythrocyte sedimentation rate and C-reactive protein) at the beginning and end of parenteral therapy and at the time of transition to oral suppressive therapy (if used).

ANTIBIOTIC THERAPY

Whenever possible, initiation of antibiotic therapy should be delayed until bone cultures can be obtained. Patients who have received antibiotics recently and do not have an acute need for surgical intervention should discontinue antibiotics for at least two weeks prior to debridement to optimize microbiologic diagnosis.

Suggested antibiotic regimens are outlined in the table (table 1)[14-19]. Antibiotic therapy should be tailored to culture and susceptibility findings when available.

Systemic therapy — Management of complex orthopedic infections usually includes a prolonged course of intravenous (IV) antibiotic therapy; data regarding use of oral antibiotic therapy are emerging.

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In one randomized trial including more than 1000 patients with bone or joint infection treated with IV or oral antibiotic therapy for at least six weeks (median duration of therapy 78 and 71 days, respectively), the rates of treatment failure within one year were comparable (14 versus 13 percent) [20]. A variety of orthopedic infections were included, including osteomyelitis with or without an associated implant; surgical debridement occurred in 92 percent of cases. Based on these data, among carefully selected patients who undergo surgical debridement and have infection caused by an organism that is susceptible to oral therapy, a course of oral antimicrobial therapy (preferably with highly bioavailable agents, perhaps with extended duration up 12 weeks) may be a reasonable consideration in some circumstances. However, the generalizability of these findings is limited by the heterogeneous patient population and open-label design, so the results should be interpreted carefully when applied to individual patients.

Empiric therapy — Empiric treatment of osteomyelitis should consist of antimicrobial therapy with activity against methicillin-resistant S. aureus (MRSA) and gram-negative organisms. Reasonable regimens include vancomycin in combination with a third- or fourth-generation cephalosporin. We avoid combined use of vancomycin with piperacillin-tazobactam, given the risk of nephrotoxicity with this combination [21]. Antibiotic therapy should be tailored to culture and susceptibility data when available.

Definitive therapy

Staphylococci

Staphylococcus aureus — In general, definitive therapy for treatment of osteomyelitis due to S. aureus consists of parenteral antibiotic therapy; regimens are summarized in the table (table 1). In addition, use of adjunctive agents for treatment of S. aureus osteomyelitis may be warranted in some circumstances. (See 'Use of adjunctive agents' below.)

Antibiotics for treatment of osteomyelitis due to methicillin-susceptible S. aureus (MSSA) include oxacillin, nafcillin, and cefazolin (table 1). Use of ceftriaxone for treatment of staphylococcal osteomyelitis is not universally accepted; in our practice, we use it as an alternative regimen for isolates with oxacillin minimum inhibitory concentration <0.5 mcg/mL in the absence of concomitant bacteremia, since once- daily dosing is a convenient outpatient regimen [22,23]. Issues related to duration of antibiotic therapy are discussed above. (See 'Clinical approach' above.)

The antibiotic of choice for treatment of osteomyelitis due to MRSA is vancomycin (table 1); it is the antibiotic agent for which there is the greatest cumulative clinical experience, although there are no controlled trials [24,25]. The Infectious Diseases Society of America (IDSA) guidelines recommend a minimum of eight weeks of antibiotic therapy for treatment of MRSA osteomyelitis [24]; we favor a six- week course of therapy if adequate debridement has been performed. (See 'Clinical approach' above.)

Acceptable alternative agents to vancomycin for treatment of osteomyelitis due to MRSA include daptomycin (and teicoplanin, where available) [26-28]. An observational study including more than 400 patients with osteomyelitis due to gram-positive pathogens noted success rates of 80 percent with daptomycin for treatment of staphylococcal osteomyelitis [28]. The optimal dosing of daptomycin for https://www.uptodate.com/...rint?search=osteomyelitis&source=search_result&selectedTitle=1~150&usage_type=default&display_rank=1[19.03.2020 15:30:21] Osteomyelitis in adults: Treatment - UpToDate

treatment of osteomyelitis is uncertain; dosing used in the preceding study ranged from 6 to 10 mg/kg/day.

Antibiotic agents that warrant further study for treatment of staphylococcal osteomyelitis include ceftaroline, telavancin, and dalbavancin [29-35]. Ceftaroline has been used successfully for treatment of osteomyelitis but has been associated with increased risk of neutropenia [30,36]. Pending further study, use of ceftaroline should be reserved for patients unable to receive other therapies [30]. Ceftaroline susceptibility must be confirmed; the prevalence of resistance is high in some regions [37]. Use of telavancin for treatment of osteomyelitis should be deferred pending further study to evaluate safety, given increased risk of adverse events observed with its use for treatment of other conditions [29,31,38]. Dalbavancin has the unique advantage of weekly intravenous dosing [32]. It has been used successfully for treatment of osteomyelitis, but should be reserved for use in patients in whom other therapies are not an option and in whom the organism is susceptible, until further data are available [32-35].

We do not favor use of trimethoprim-sulfamethoxazole, linezolid, tedizolid, clindamycin, fluoroquinolones, quinupristin-dalfopristin, or tigecycline for definitive therapy of osteomyelitis due to S. aureus. A regimen of trimethoprim-sulfamethoxazole with rifampin is advocated in some treatment guidelines [24] but not others [39]; data to support its use are limited [12,40,41]. Prolonged use of linezolid is limited by bone marrow toxicity, peripheral and optic neuropathy, lactic acidosis, and drug-drug interactions [42-44]. Tedizolid has not been studied sufficiently in osteomyelitis. Prolonged use of clindamycin has been associated with antibiotic-associated diarrhea and Clostridioides (formerly Clostridium) difficile infection. Fluoroquinolones have good bone penetration but are associated with inducible resistance to S. aureus when used as monotherapy.

Coagulase-negative staphylococci — Most coagulase-negative staphylococci are methicillin resistant (an exception is Staphylococcus lugdunensis, which is almost universally methicillin susceptible). (See "Staphylococcus lugdunensis".)

Empiric treatment for osteomyelitis due to coagulase-negative staphylococci should consists of an agent with activity against methicillin-resistant staphylococci. If susceptibility testing demonstrates methicillin susceptibility, a beta-lactam with activity against methicillin-susceptible staphylococci should be used (table 1).

In addition, use of adjunctive agents for treatment staphylococcal osteomyelitis may be warranted in some circumstances. (See 'Use of adjunctive agents' below.)

Use of adjunctive agents — Agents that may be used adjunctively in the setting of definitive therapy for treatment of staphylococcal osteomyelitis include rifampin and fusidic acid.

We are in agreement with some experts who favor use of rifampin (in combination with at least one other anti-staphylococcal agent) for its activity against microorganisms in biofilms, given the importance of biofilms in the pathophysiology of staphylococcal osteomyelitis (particularly in the setting of hardware) [24,45,46]. However, others oppose use of adjunctive rifampin given limited evidence for improved

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outcomes over standard antimicrobial therapy.

Clinical circumstances in which rifampin may be most useful include osteomyelitis in the setting of prosthetic material and osteomyelitis in which therapeutic options are limited. Data may be extrapolated from literature on treatment of prosthetic joint infection to support use of rifampin in the treatment of infections involving other types of orthopedic hardware [47,48]. Use of rifampin must be weighed against the likelihood of toxicity and drug interactions [49]. (See "Prosthetic joint infection: Treatment", section on 'Debridement and retention of prosthesis'.)

Rifampin must be combined with another active antibacterial agent because rapid emergence of resistance in the setting of rifampin monotherapy is common. Rifampin should be initiated several days after surgical debridement; resistance is less likely to emerge when the burden of organisms has been reduced [46,50]. We continue rifampin for the duration of definitive therapy (parenteral therapy or highly bioavailable oral antibiotic therapy). [46]. We do not use rifampin during suppressive therapy. (See "Rifamycins (rifampin, rifabutin, rifapentine)" and "Prosthetic joint infection: Treatment".)

Fusidic acid (not available in the United States) may be used as adjunctive oral therapy in the treatment of chronic osteomyelitis [51-53].

Gram-negative organisms — For treatment of osteomyelitis due to gram-negative organisms, we favor fluoroquinolones (if susceptibility testing confirms sensitivity) since they have high bone penetration with oral administration [19,54]. However, some avoid use of these agents in the setting of fracture, due to possible adverse effects on fracture healing [54].

Other antibiotics for treatment of osteomyelitis due to gram-negative organisms include parenteral beta- lactams and carbapenems. Antibiotic dosing is summarized in the table (table 1).

Among the gram-negative organisms, management of osteomyelitis caused by Pseudomonas aeruginosa may be more difficult than other organisms [55,56]. In one cohort study including 66 patients with osteomyelitis due to P. aeruginosa who underwent surgical debridement, most patients were treated with two weeks of intravenous therapy followed by oral fluoroquinolone therapy (median duration of treatment 45 days); clearance of infection was demonstrated in 94 percent of cases [56]. Most patients received monotherapy; no emergence of resistance was observed.

Streptococci and enterococci — Osteomyelitis due to penicillin-susceptible streptococci may be treated with penicillin; ceftriaxone is also acceptable and is more convenient for outpatient administration (table 1).

For treatment of osteomyelitis due to enterococci, it is unclear whether combination therapy is superior to monotherapy, particularly if thorough debridement is performed [57]. We favor combination therapy in the setting of retained hardware; the regimen of ampicillin and ceftriaxone is generally well tolerated [58]. However, if antibiotic-impregnated material containing gentamicin is implanted at the time of debridement, monotherapy is likely sufficient; in such cases, we favor treatment with intravenous ampicillin or penicillin (table 1). https://www.uptodate.com/...rint?search=osteomyelitis&source=search_result&selectedTitle=1~150&usage_type=default&display_rank=1[19.03.2020 15:30:21] Osteomyelitis in adults: Treatment - UpToDate

Suppressive therapy — Long-term antibiotic suppression with an oral agent is warranted for patients with retained hardware and/or necrotic bone not amenable to debridement, following completion of parenteral therapy with resolution of clinical signs of acute infection. (See 'Retained hardware' above.)

Duration of therapy — Issues related to duration of antibiotic therapy are discussed above. (See 'Clinical approach' above.)

Local antibiotic delivery — Local antimicrobials mixed with absorbable carriers (eg, calcium sulfate beads) or nonabsorbable carriers (eg, polymethyl methacrylate beads or cement) placed in and around the fracture site may be useful as an adjunct to systemic antibiotics for prevention or treatment of infection [59].

Data are most robust for polymethylmethacrylate beads; these are typically removed within two to four weeks. Antibiotic-impregnated calcium sulfate beads are absorbable; they have been used as a bone substitute and delivery system for antibiotics repairing bony defects in open fractures caused by combat- related injuries [59,60].

SPECIAL POPULATIONS

Osteomyelitis associated with trauma — Issues related to osteomyelitis associated with trauma are discussed separately. (See "Osteomyelitis associated with open fractures in adults".)

Prosthetic joint infection — Issues related to prosthetic joint infection are discussed separately. (See "Prosthetic joint infection: Treatment".)

Osteomyelitis in sickle cell disease — Issues related to osteomyelitis in sickle cell disease are discussed separately. (See "Acute and chronic bone complications of sickle cell disease", section on 'Osteomyelitis and septic arthritis'.)

ADJUNCTIVE THERAPIES

Hyperbaric oxygen (HBO) has been suggested as an adjunctive therapy in patients with refractory osteomyelitis [61,62]. We do not favor use of HBO for treatment of osteomyelitis, given lack of sufficient data.

Issues related to HBO are discussed further separately. (See "Hyperbaric oxygen therapy".)

OUTCOME

Success rates for treatment of osteomyelitis reported in the literature range from 60 to 90 percent [12]. The success rate can be highly variable given the heterogeneity in completeness of debridement, the

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possibility of concomitant vascular insufficiency at the site of infection, heterogeneity in completeness of debridement, and other factors.

SOCIETY GUIDELINE LINKS

SUMMARY AND RECOMMENDATIONS

● In general, management of nonhematogenous osteomyelitis consists of operative debridement for removal of necrotic material and culture of involved tissue and bone, followed by antimicrobial therapy for eradication of infection. (See 'Nonhematogenous osteomyelitis' above.)

• In the absence of orthopedic hardware (see 'Absence of orthopedic hardware' above):

- Patients with residual infected bone that is not amenable to complete removal should be treated with a prolonged duration antibiotic therapy, guided by antimicrobial susceptibility data (table 1). The optimal duration of antibiotic therapy is uncertain; we favor continuing antimicrobial therapy at least six weeks from the last debridement. (See 'Residual infected bone present' above.)

- Patients who undergo amputation or complete removal of all involved bone warrant a relatively short course of antibiotic therapy. (See 'No residual infected bone' above.)

• In the presence of orthopedic hardware (see 'Presence of orthopedic hardware' above):

- Following debridement, patients should be treated with a prolonged duration of intravenous antibiotic therapy, guided by antimicrobial susceptibility data (table 1). The optimal duration is uncertain; we favor six weeks of therapy. (See 'No retained hardware' above.)

- Thereafter, patients with retained hardware and/or necrotic bone not amenable to debridement should receive long-term antibiotic suppression with an oral agent, guided by antimicrobial susceptibility data (table 2). (See 'Retained hardware' above.)

● Empiric treatment of nonhematogenous osteomyelitis should consist of antimicrobial therapy with activity against methicillin-resistant Staphylococcus aureus (MRSA) and gram-negative organisms. Reasonable regimens include vancomycin in combination with a third- or fourth-generation cephalosporin. (See 'Empiric therapy' above.)

● For treatment of osteomyelitis due to MRSA, we suggest vancomycin (Grade 2C); daptomycin is an acceptable alternative agent (table 1). (See 'Staphylococcus aureus' above.)

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● For patients with S. aureus osteomyelitis and retained hardware, we suggest adjunctive use of rifampin (in combination with at least one other anti-staphylococcal agent) (Grade 2C). Use of rifampin must be weighed against the likelihood of toxicity and drug interactions. (See 'Use of adjunctive agents' above.)

● Treatment of hematogenous (nonvertebral) osteomyelitis consists of parenteral antibiotic therapy. In addition, surgical debridement is warranted in the setting of subperiosteal collection and/or in the setting of concomitant joint infection. Empiric antibiotic coverage for treatment of hematogenous osteomyelitis should include activity against MRSA and aerobic gram-negative bacilli. Once an etiologic organism is isolated, the antibiotic regimen should be tailored to susceptibility data. The optimal duration of antibiotic therapy is uncertain; in general, at least four weeks of parenteral therapy from the last major debridement are warranted. (See 'Hematogenous (nonvertebral) osteomyelitis' above.)

ACKNOWLEDGMENT

The editorial staff at UpToDate would like to acknowledge Tahaniyat Lalani, MBBS, MHS, who contributed to an earlier version of this topic review.

Use of UpToDate is subject to the Subscription and License Agreement.

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44. Bassetti M, Vitale F, Melica G, et al. Linezolid in the treatment of Gram-positive prosthetic joint infections. J Antimicrob Chemother 2005; 55:387.

45. Henry NK, Rouse MS, Whitesell AL, et al. Treatment of methicillin-resistant Staphylococcus aureus experimental osteomyelitis with ciprofloxacin or vancomycin alone or in combination with rifampin. Am J Med 1987; 82:73.

46. Zimmerli W, Widmer AF, Blatter M, et al. Role of rifampin for treatment of orthopedic implant-related staphylococcal infections: a randomized controlled trial. Foreign-Body Infection (FBI) Study Group. JAMA 1998; 279:1537.

47. El Helou OC, Berbari EF, Lahr BD, et al. Efficacy and safety of rifampin containing regimen for

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staphylococcal prosthetic joint infections treated with debridement and retention. Eur J Clin Microbiol Infect Dis 2010; 29:961.

48. Lora-Tamayo J, Murillo O, Iribarren JA, et al. A large multicenter study of methicillin-susceptible and methicillin-resistant Staphylococcus aureus prosthetic joint infections managed with implant retention. Clin Infect Dis 2013; 56:182.

49. Perlroth J, Kuo M, Tan J, et al. Adjunctive use of rifampin for the treatment of Staphylococcus aureus infections: a systematic review of the literature. Arch Intern Med 2008; 168:805.

50. Norden CW, Bryant R, Palmer D, et al. Chronic osteomyelitis caused by Staphylococcus aureus: controlled clinical trial of nafcillin therapy and nafcillin-rifampin therapy. South Med J 1986; 79:947.

51. Howden BP, Grayson ML. Dumb and dumber--the potential waste of a useful antistaphylococcal agent: emerging fusidic acid resistance in Staphylococcus aureus. Clin Infect Dis 2006; 42:394.

52. Pushkin R, Iglesias-Ussel MD, Keedy K, et al. A Randomized Study Evaluating Oral Fusidic Acid (CEM-102) in Combination With Oral Rifampin Compared With Standard-of-Care Antibiotics for Treatment of Prosthetic Joint Infections: A Newly Identified Drug-Drug Interaction. Clin Infect Dis 2016; 63:1599.

53. Marsot A, Ménard A, Dupouey J, et al. Population pharmacokinetics of rifampicin in adult patients with osteoarticular infections: interaction with fusidic acid. Br J Clin Pharmacol 2017; 83:1039.

54. Huddleston PM, Steckelberg JM, Hanssen AD, et al. Ciprofloxacin inhibition of experimental fracture healing. J Bone Joint Surg Am 2000; 82:161.

55. Gentry LO, Rodriguez GG. Oral ciprofloxacin compared with parenteral antibiotics in the treatment of osteomyelitis. Antimicrob Agents Chemother 1990; 34:40.

56. Laghmouche N, Compain F, Jannot AS, et al. Successful treatment of Pseudomonas aeruginosa osteomyelitis with antibiotic monotherapy of limited duration. J Infect 2017; 75:198.

57. El Helou OC, Berbari EF, Marculescu CE, et al. Outcome of enterococcal prosthetic joint infection: is combination systemic therapy superior to monotherapy? Clin Infect Dis 2008; 47:903.

58. Euba G, Lora-Tamayo J, Murillo O, et al. Pilot study of ampicillin-ceftriaxone combination for treatment of orthopedic infections due to Enterococcus faecalis. Antimicrob Agents Chemother 2009; 53:4305.

59. Hake ME, Young H, Hak DJ, et al. Local antibiotic therapy strategies in orthopaedic trauma: Practical tips and tricks and review of the literature. Injury 2015; 46:1447.

60. Helgeson MD, Potter BK, Tucker CJ, et al. Antibiotic-impregnated calcium sulfate use in combat- related open fractures. Orthopedics 2009; 32:323.

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61. Mader JT, Guckian JC, Glass DL, Reinarz JA. Therapy with hyperbaric oxygen for experimental osteomyelitis due to Staphylococcus aureus in rabbits. J Infect Dis 1978; 138:312.

62. Goldman RJ. Hyperbaric oxygen therapy for wound healing and limb salvage: a systematic review. PM R 2009; 1:471.

Topic 114350 Version 16.0

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†, ,¶¶

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ΔΔ

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GRAPHICS

Antibiotic therapy for treatment of osteomyelitis or prosthetic joint infection in adults

Infectious agent Antibiotic regimen Dosing

Empiric therapy Vancomycin PLUS a third- or fourth-generation As summarized below cephalosporin (such as ceftriaxone, ceftazidime, or cefepime)

Pathogen-specific therapy

Staphylococci, Nafcillin 2 g IV every 4 hours methicillin Oxacillin 2 g IV every 4 hours susceptible* Cefazolin 2 g IV every 8 hours

Flucloxacillin 2 g IV every 6 hours

Ceftriaxone¶ 2 g IV every 24 hours

Staphylococci, Regimen of choice: methicillin VancomycinΔ 20 mg/kg loading dose, then 15 mg/kg/dose IV resistant* every 12 hours, not to exceed 2 g per dose initially

Alternative regimens:◊

Daptomycin§ 6 to 10 mg/kg IV once daily

Teicoplanin (where available)¥‡ 12 mg/kg IV every 12 hours for 3 to 5 doses, followed by 12 mg/kg once daily

Staphylococci, Rifampin 300 to 450 mg orally twice daily adjunctive agents* Fusidic acid (where available)¥ 500 mg orally 3 times daily

Gram-negative Ciprofloxacin†,**,¶¶ 750 mg orally twice daily or 400 mg IV every organisms 12 hours; if treating Pseudomonas, increase IV dose to 400 mg IV every 8 hours

Levofloxacin**,¶¶ 750 mg orally or IV once daily

CeftriaxoneΔΔ 2 g IV every 24 hours

Ceftazidime** 2 g IV every 8 hours

Cefepime** 2 g IV every 8 to 12 hours

ErtapenemΔΔ 1 g IV every 24 hours

Meropenem** 1 g IV every 8 hours

Enterococci◊◊ Monotherapy regimens:

Ampicillin 12 g IV every 24 hours, either continuously or in 6 equally divided doses

Aqueous crystalline penicillin G 20 to 24 million units IV every 24 hours, either continuously or in 6 equally divided doses

VancomycinΔ 20 mg/kg loading dose, then 15 mg/kg IV every 12 hours, not to exceed 2 g per dose

Daptomycin§ 6 to 10 mg/kg IV once daily

Teicoplanin (where available)¥‡ 12 mg/kg IV every 12 hours for 3 to 5 doses, followed by 12 mg/kg once daily

Combination therapy regimen:

Ampicillin 12 g IV every 24 hours, given either continuously or in 6 equally divided doses

PLUS

Ceftriaxone 2 g IV every 12 to 24 hours

Streptococci, One of the following: penicillin sensitive https://www.uptodate.com/...rint?search=osteomyelitis&source=search_result&selectedTitle=1~150&usage_type=default&display_rank=1[19.03.2020 15:30:21] Osteomyelitis in adults: Treatment - UpToDate

Aqueous crystalline penicillin G 20 to 24 million units IV every 24 hours, either continuously or in 6 equally divided doses

Ampicillin 12 g IV every 24 hours, either continuously or in 6 equally divided doses

Ceftriaxone 2 g IV every 24 hours

VancomycinΔ 20 mg/kg loading dose, then 15 mg/kg/dose IV every 12 hours, not to exceed 2 g per dose, initially

Cutibacterium One of the following: (formerly Aqueous crystalline penicillin G 20 million units IV every 24 hours, either Propionibacterium) continuously or in 6 divided doses acnes§§ Ceftriaxone 2 g IV every 24 hours

In stable patients, antibiotics may be held pending establishment of microbiologic diagnosis or obtaining cultures from bone debridement or biopsy. The total duration of antibiotic therapy depends on individual patient circumstances (refer to the UpToDate content on treatment of osteomyelitis and prosthetic joint infection for further discussion). The doses in this table are intended for adults with normal renal function. The doses of many of these agents must be adjusted in the setting of renal insufficiency; refer to the Lexicomp drug-specific monographs for renal dose adjustments.

IV: intravenously; PJI: prosthetic joint infection. * For patients with Staphylococcus aureus PJI and residual hardware following surgery, we favor use of adjunctive rifampin. To mitigate the emergence of resistance, rifampin should not be started until the patient has received several days of antistaphylococcal therapy. We favor administration of rifampin 450 orally twice daily; the dose may be reduced to 300 mg orally twice daily in the setting of nausea. There should be careful screening drug-drug interactions prior to initiation of rifampin. ¶ Use of ceftriaxone for treatment of staphylococcal osteomyelitis is not universally accepted. In our practice, we use it as an alternative regimen for isolates with oxacillin minimum inhibitory concentration <0.5 mcg/mL in the absence of concomitant bacteremia; once-daily dosing is a convenient outpatient regimen. Δ In adults, vancomycin is dosed based on actual body weight. Target troughs for vancomycin should be chosen with the guidance of a local infectious disease physician based on the pathogen, in vitro susceptibility, and the use of rifampin or local vancomycin therapy, with a target trough concentration of at least 10 mcg/mL. It is unknown if a higher vancomycin trough level of 15 to 20 mcg/mL is routinely needed. Refer to the UpToDate topic review on vancomycin parenteral dosing and serum concentration monitoring in adults. ◊ Ceftaroline has been used successfully for treatment of osteomyelitis but has been associated with increased risk of neutropenia. Pending further study, use of ceftaroline should be reserved for patients unable to receive other therapies. Ceftaroline susceptibility must be confirmed; the prevalence of resistance is high in some regions. Daptomycin may be used for vancomycin-resistant enterococci; confirm susceptibility. § Standard daptomycin dosing (as approved by the US Food and Drug Administration) for treatment of bacteremia or osteomyelitis is 6 mg/kg IV once daily. Because daptomycin exhibits concentration-dependent killing, some experts recommend doses of up to 8 to 10 mg/kg IV once daily, which appear safe; further study is needed. ¥ Not available in the United States. Fusidic acid should not be used alone; it must be combined with a second active agent to reduce the likelihood of selection for drug resistance. When rifampin is combined with fusidic acid, fusidic levels may be reduced. ‡ The teicoplanin dose should be adjusted to attain a trough concentration of >20 mcg/mL. † Oral ciprofloxacin at dose shown in table achieves therapeutic levels for treatment of Pseudomonas aeruginosa. ** Ciprofloxacin, levofloxacin, ceftazidime, cefepime, and meropenem have activity against P. aeruginosa; confirm susceptibility. ¶¶ The possibility of prolonged QTc interval, tendinopathy, neuropathy, or development of an aneurysm should be reviewed and monitored when using fluoroquinolones. For more information, please refer to the UpToDate topic on fluoroquinolones. ΔΔ Ceftriaxone and ertapenem have no activity against P. aeruginosa, but are appropriate for other gram-negative organisms, if susceptible. ◊◊ For treatment of infection due to penicillin-susceptible enterococci, it is unclear whether combination therapy is superior to monotherapy, particularly if thorough debridement is performed. In the setting of retained hardware, we favor combination therapy for PJI due to Enterococcus faecalis with ampicillin and ceftriaxone. We do not use this approach for treatment of PJI due to non-faecalis species of penicillin-susceptible enterococci because synergy with these agents in vitro is variable and clinical data are not available in patients with PJI due to non-faecalis species [11]. If antibiotic-impregnated material containing gentamicin is implanted at the time of debridement, then monotherapy is likely sufficient and we favor treatment with either intravenous ampicillin or penicillin (vancomycin or daptomycin are acceptable alternative agents for patients with proven beta- lactam hypersensitivity). For treatment of infection due to penicillin-resistant enterococci, the preferred agent is vancomycin; daptomycin or teicoplanin (where available) are acceptable alternative agents. §§ For patients with Cutibacterium spp infection and beta-lactam hypersensitivity, reasonable alternative agents include vancomycin, a tetracycline (doxycycline or minocycline), or moxifloxacin.

Data from: 1. Osmon DR, Berbari EF, Berendt AR, et al. Diagnosis and management of prosthetic joint infection: clinical practice https://www.uptodate.com/...rint?search=osteomyelitis&source=search_result&selectedTitle=1~150&usage_type=default&display_rank=1[19.03.2020 15:30:21] Osteomyelitis in adults: Treatment - UpToDate

guidelines by the Infectious Diseases Society of America. Clin Infect Dis. 2013; 56:e1. 2. Berbari EF, Kanj SS, Kowalski TJ, et al. 2015 Infectious Diseases Society of America (IDSA) clinical practice guidelines for the diagnosis and treatment of native vertebral osteomyelitis in adults. Clin Infect Dis 2015; 61:e26. 3. Figueroa DA, Mangini E, Amodio-Groton M, et al. Safety of high-dose intravenous daptomycin treatment: three-year cumulative experience in a clinical program. Clin Infect Dis 2009; 49:177. 4. Benvenuto M, Benziger DP, Yankelev S, Vigliani G. Pharmacokinetics and tolerability of daptomycin at doses up to 12 milligrams per kilogram of body weight once daily in healthy volunteers. Antimicrob Ther Chemother 2006; 50:3245. 5. Liu C, Bayer A, Cosgrove SE, et al. Clinical practice guidelines by the Infectious Diseases Society of America for the treatment of methicillin-resistant Staphylococcus aureus infections in adults and children. Clin Infect Dis 2011; 52:285. 6. Teicoplanin. The UK electronic Medicines Compendium (eMC) summary of product characteristics. Last updated February 01, 2018. UK electronic Medicines Compendium. (Available online at https://www.medicines.org.uk/emc/ (Accessed January 28, 2019)). 7. Sodium fusidate. The UK electronic Medicines Compendium (eMC) summary of product characteristics. Last updated August 30, 2018. UK electronic Medicines Compendium. (Available online at https://www.medicines.org.uk/emc/ (Accessed January 28, 2019)). 8. Euba G, Lora-Tamayo J, Murillo O, et al. Pilot study of ampicillin-ceftriaxone combination for treatment of orthopedic infections due to Enterococcus faecalis. Antimicrob Agents Chemother 2009; 53:4305. 9. Calhoun JH, Manring MM. Adult osteomyelitis. Infect Dis Clin North Am 2005; 19:765. 10. Pushkin R, Iglesias-Ussel MD, Keedy K, et al. A randomized study evaluating oral fusidic acid (CEM-102) in combination with oral rifampin compared with standard-of-care antibiotics for treatment of prosthetic joint infections: A newly identified drug-drug interaction. Clin Infect Dis 2016; 63:1599. 11. Lorenzo MP, Kidd JM, Jenkins SG, et al. In vitro activity of ampicillin and ceftriaxone against ampicillin-susceptible Enterococcus faecium. J Antimicrob Chemother 2019; 74:2269.

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Suppression of osteomyelitis or prosthetic joint infection in adults: Oral antibiotic regimens*

Infectious agent Antibiotic regimen¶ Dosing

Staphylococci, One of the following: methicillin Cefadroxil 500 to 1000 mg twice daily susceptible Cephalexin 500 mg 3 or 4 times daily, or 1000 mg 2 or 3 times daily

Dicloxacillin 500 mg 3 or 4 times daily

Flucloxacillin 500 mg 3 or 4 times daily

Staphylococci, One of the following: methicillin Trimethoprim-sulfamethoxazole 1 double-strength tablet twice daily resistantΔ Doxycycline 100 mg twice daily

Minocycline 100 mg twice daily

Clindamycin 600 mg 3 times daily

Gram-negative One of the following: organisms Trimethoprim-sulfamethoxazole 1 double-strength tablet twice daily

Ciprofloxacin◊ 500 mg twice daily

Levofloxacin◊ 500 mg once daily

Penicillin-sensitive One of the following: streptococci and Amoxicillin 500 mg 2 to 3 times daily enterococci Penicillin V K 500 mg 2 to 3 times daily

Cutibacterium One of the following: (formerly Amoxicillin 500 mg 2 to 3 times daily Propionibacterium) acnes Penicillin V K 500 mg 2 to 3 times daily

The doses recommended above are intended for adults with normal renal function; the doses of some of these agents must be adjusted in patients with renal insufficiency. Refer to the Lexicomp drug-specific monographs for renal dose adjustments.

PJI: Prosthetic joint infection. * Initial treatment of PJI consists of definitive antibiotic therapy (refer to the separate UpToDate table); suppressive therapy is warranted only for individuals with retained hardware and/or necrotic bone not amenable to complete debridement. The optimal duration of oral suppressive antibiotic therapy is uncertain. Refer to the UpToDate topic on the treatment of PJI for further discussion. ¶ The choice of antibiotic regimen should be based on susceptibility, as well as patient drug allergies, intolerances, and potential drug-drug interactions or contraindications to a specific agent. Δ The agents listed for methicillin-resistant staphylococci may be used for suppression of methicillin-susceptible staphylococci in patients with beta-lactam allergy or intolerance, provided the organism is susceptible. ◊ Ciprofloxacin and levofloxacin have activity against Pseudomonas aeruginosa.

Data from: 1. Osmon DR, Berbari EF, Berendt AR, et al. Diagnosis and management of prosthetic joint infection: clinical practice guidelines by the Infectious Diseases Society of America. Clin Infect Dis. 2013; 56:e1. 2. Berbari EF, Kanj SS, Kowalski TJ, et al. 2015 Infectious Diseases Society of America (IDSA) clinical practice guidelines for the diagnosis and treatment of native vertebral osteomyelitis in adults. Clin Infect Dis 2015; 61:e26.

Graphic 119913 Version 4.0

Contributor Disclosures

Douglas R Osmon, MD Nothing to disclose Aaron J Tande, MD Nothing to disclose Denis Spelman, MBBS, FRACP, FRCPA, MPH Nothing to disclose Elinor L Baron, MD, DTMH Nothing to disclose

Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are addressed by

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Contributor Disclosures

Douglas R Osmon, MD Nothing to disclose Aaron J Tande, MD Nothing to disclose Denis Spelman, MBBS, FRACP, FRCPA, MPH Nothing to disclose Elinor L Baron, MD, DTMH Nothing to disclose

Conflict of interest policy

https://www.uptodate.com/...rint?search=osteomyelitis&source=search_result&selectedTitle=1~150&usage_type=default&display_rank=1[19.03.2020 15:30:21] Osteomyelitis associated with open fractures in adults - UpToDate

Official reprint from UpToDate® www.uptodate.com ©2020 UpToDate, Inc. and/or its affiliates. All Rights Reserved. Print Options Print | Back Text References Graphics Osteomyelitis associated with open fractures in adultsContributor Disclosures Author: Steven K Schmitt, MD, FIDSA Section Editor: Denis Spelman, MBBS, FRACP, FRCPA, MPH Deputy Editor: Elinor L Baron, MD, DTMH

All topics are updated as new evidence becomes available and our peer review process is complete.

Literature review current through: Feb 2020. | This topic last updated: Nov 25, 2019.

INTRODUCTION

Osteomyelitis may develop as a result of contamination of open fractures [1-3].

The epidemiology, microbiology, clinical manifestations, treatment, and prevention of osteomyelitis in the setting of open fractures will be reviewed here.

General principles of fracture management are discussed separately. (See "General principles of fracture management: Early and late complications", section on 'Open fractures' and "General principles of fracture management: Early and late complications", section on 'Osteomyelitis'.)

General issues related to osteomyelitis are discussed separately. (See "Osteomyelitis in adults: Clinical manifestations and diagnosis" and "Osteomyelitis in adults: Treatment".)

Issues related to prosthetic joint infections are discussed separately. (See "Prosthetic joint infection: Epidemiology, microbiology, clinical manifestations, and diagnosis" and "Prosthetic joint infection: Treatment".)

Issues related to infection following nail puncture are discussed separately. (See "Pseudomonas aeruginosa skin and soft tissue infections", section on 'Infection following nail puncture'.)

Issues related to injury associated with bites are discussed separately. (See "Animal bites (dogs, cats, and other animals): Evaluation and management" and "Human bites: Evaluation and management".)

Issues related to injury associated with water are discussed separately. (See "Soft tissue infections following water exposure".)

EPIDEMIOLOGY

Osteomyelitis can occur in up to 25 percent of open fractures; the risk depends upon the following factors

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[4-10]:

● Severity of injury, including whether concurrent vascular and/or neurologic damage is present ● Degree of bacterial contamination ● Adequacy of surgical debridement ● Administration of antibiotics (including the timing as well as the type)

In one review including more than 1100 open fracture wounds, the risk of infection with open tibia fracture was twice as high as for open fracture of other sites (10.5 versus 5.3 percent) [7]. The infection rate after open hand fracture is relatively low; in one review including twelve articles (4 prospective, 8 retrospective) and 1669 open fractures of the hand, the infection rate was approximately 3 to 4 percent [11].

MICROBIOLOGY

Microorganisms can be introduced directly into bone in the setting of fracture or via contiguous spread from injury to overlying soft tissue. They proliferate in the presence of devitalized tissues containing clotted blood and necrotic bone.

Pathogens may include skin flora, environmental organisms, or nosocomial pathogens. The most common organisms include Staphylococcus aureus, coagulase-negative staphylococci, and aerobic gram-negative bacilli. Other less commonly implicated pathogens include enterococci, anaerobes, fungi, and mycobacteria [6,12-18]. If the fracture is associated with water, infection may be caused by Pseudomonas, Aeromonas, or Vibrio species. (See "Soft tissue infections following water exposure".)

The microbiologic diagnosis is established via cultures obtained at the time of debridement for possible infection, rather than at the time of initial debridement following fracture. Cultures obtained at the time of initial debridement correlate with established pathogens of osteomyelitis in only 25 percent of cases [19,20]. Not all microbes colonizing the wound at the time of injury cause sustained infection in the bone, and pathogens not present at the initial injury may colonize and infect wounds subsequently.

CLINICAL MANIFESTATIONS

The approach to classification of open fractures is summarized in the table (table 1).

Acute osteomyelitis following fracture usually presents with gradual progression of dull localized pain over several days. Local findings (tenderness, warmth, erythema, swelling) and systemic symptoms (fever, rigors) may be present. Decreased range of motion, point tenderness, and joint effusions may be seen but are also present with uninfected fractures, making clinical diagnosis potentially difficult.

In some cases, osteomyelitis presents with few symptoms or signs. This is more common with subacute or chronic infections, with infections of the hip, pelvis, or vertebrae, and in young patients.

Chronic osteomyelitis may present with pain, erythema, or swelling, sometimes in association with a draining sinus tract. Fractures that are healing slower than expected or that remain extremely painful despite adequate immobilization may be a sign that osteomyelitis is present.

After open fracture, non-union is the most common consequence and manifestation of osteomyelitis. Non-unions commonly present with persistent pain, swelling, or instability beyond the time when healing should normally have occurred.

Additional manifestations of osteomyelitis and non-union associated with fracture are discussed separately. (See "General principles of fracture management: Early and late complications", section on 'Osteomyelitis'.)

DIAGNOSIS

The approach to diagnosis of osteomyelitis following open fracture is the same as the approach to diagnosis of osteomyelitis due to other causes; this is discussed separately. (See "Osteomyelitis in adults: Clinical manifestations and diagnosis" and "Approach to imaging modalities in the setting of suspected nonvertebral osteomyelitis".)

TREATMENT

Following a fracture, initial management of osteomyelitis or infected non-union consists of surgical debridement with irrigation, obtaining bone biopsy for culture, fracture fixation (if needed), and antimicrobial therapy tailored to culture and susceptibility data [15,21-31].

In type III wounds, closure of soft tissue may require flaps or grafts of skin or tissue [32].

To achieve optimal union in the setting of concomitant osteomyelitis, it may be necessary to administer parenteral antibiotic therapy for as long as fixation hardware remains in place. Once fracture union is achieved, fixation hardware should be removed (if possible), with additional debridement.

The approach to antibiotic therapy for patients with retained hardware is discussed separately. (See "Osteomyelitis in adults: Treatment", section on 'Retained hardware'.)

The approach to antibiotic therapy for patients with no retained hardware is discussed separately. (See "Osteomyelitis in adults: Treatment", section on 'No retained hardware'.)

Antibiotic selection and other issues related to treatment of osteomyelitis are discussed in detail separately. (See "Osteomyelitis in adults: Treatment", section on 'Antibiotic therapy'.)

PREVENTION

Measures for prevention of osteomyelitis following open fracture include prompt debridement, surgical fixation (if needed), and antibiotic therapy [1].

Initial fracture management — General principles of acute fracture management are discussed separately. (See "General principles of acute fracture management" and "General principles of fracture management: Early and late complications", section on 'Open fractures'.)

In general, initial fracture management consists of thorough irrigation and debridement. Some have suggested that open fractures should be debrided within six hours of injury. No definitive association has been made between delayed debridement and higher infection rates; further study is needed [33-35].

The decision regarding use of fixation hardware for stabilization is made on a case-by-case basis.

At the time of initial debridement, there is no need for operative routine cultures. If subsequent debridement is performed for suspected infection, collection of operative cultures is warranted at that time. (See 'Microbiology' above.)

Once union is achieved, fixation hardware may be removed and additional debridement performed if needed. Final steps include bone grafting (if needed) and wound closure [22-31,36].

Primary closure may be reasonable for debrided wounds with no contamination, good residual soft tissue, and good vascular supply [37]. Delayed wound closure is generally warranted in Gustilo type II or III fractures (table 1).

Antibiotics after open fracture — The use of antimicrobial agents for dirty procedures or established infection is classified as treatment of presumed infection, rather than prophylaxis. (See "Antimicrobial prophylaxis for prevention of surgical site infection in adults", section on 'Wound classification'.)

Following open fracture, prompt administration of antibiotics (ideally within six hours) is warranted to reduce the risk of osteomyelitis [2,3,38-40]. This approach is supported by a meta-analysis including 913 patients with open fractures [36]; use of antibiotics was associated with an absolute reduction in infection of 0.08 (95% CI 0.04-0.12) [36].

Antibiotic selection — Antibiotic regimens for patients with open fractures are summarized in the table (table 2).

For patients with type I and type II fractures (table 1), antibiotic therapy should include activity against gram-positive organisms. Cefazolin is a reasonable regimen; for patients at risk for methicillin-resistant S. aureus (table 3), gram-positive coverage should consist of vancomycin. Dosing is summarized in the table (table 2).

For patients with type III fractures (table 1), antibiotic therapy should include activity against gram- negative organisms (in addition to gram-positive coverage outlined above) [2,41]. We are in agreement with the EAST Guidelines which recommend gentamicin; ceftriaxone (monotherapy) is an acceptable alternative [2,42]. Dosing is summarized in the table (table 2). https://www.uptodate.com/...yelitis-associated-with-open-fractures-in-adults/print?search=osteomyelitis&topicRef=7668&source=see_link[19.03.2020 15:31:01] Osteomyelitis associated with open fractures in adults - UpToDate

For patients with open fracture associated with soil contamination, we favor addition of metronidazole to the above regimens, for coverage of Clostridium spp.

For patients with open fracture associated with freshwater contamination, we favor piperacillin- tazobactam for activity against gram-negative pathogens such as Pseudomonas and Aeromonas species.

For patients with open fracture associated with seawater contamination, we favor piperacillin-tazobactam (as for freshwater) as well as doxycycline for activity against Vibrio species. Dosing is summarized in the table (table 2).

Data to guide the above approach to antibiotic selection are limited, and the optimal approach is uncertain. Our approach is guided by the typical microbiology of such infections as well as general trends in antimicrobial resistance.

Duration — The duration of antibiotic therapy depends on the classification of the fracture (table 1) [2,3,43,44]:

● For Gustilo type I and II open fractures, antibiotics may be discontinued 24 hours after wound closure.

● For Gustilo type III open fractures, antibiotics may be discontinued after 72 hours or within a day after soft tissue injuries have been closed.

Prolonged administration of antibiotics does not reduce the risk of infection and can lead to the development of resistant organisms [3,45].

Tetanus prophylaxis — Open fractures are tetanus-prone wounds [46,47]. The patient's tetanus immunization status should be determined; tetanus toxoid, diphtheria-tetanus-acellular pertussis, booster tetanus toxoid-reduced diphtheria toxoid-acellular pertussis, or tetanus-diphtheria toxoids adsorbed should be administered as indicated (table 4). The need for tetanus immune globulin should also be assessed (table 4). (See "Tetanus".)

SOCIETY GUIDELINE LINKS

SUMMARY

● Osteomyelitis may develop as a result of contamination of open fractures in up to 25 percent of

cases. Microorganisms can be introduced directly into bone in the setting of open fractures or via contiguous spread from injury to overlying soft tissue. Pathogens may include skin flora, environmental organisms, or nosocomial pathogens. (See 'Epidemiology' above and 'Microbiology' above.)

● The approach to classification of open fractures is summarized in the table (table 1). The approach to diagnosis of osteomyelitis following open fracture is the same as the approach to diagnosis of osteomyelitis due to other causes; this is discussed separately. (See 'Clinical manifestations' above and "Osteomyelitis in adults: Clinical manifestations and diagnosis".)

● Following a fracture, initial management of osteomyelitis or infected non-union consists of surgical debridement with irrigation, obtaining bone biopsy for culture, fracture fixation (if needed), and antimicrobial therapy tailored to culture and susceptibility data. To achieve optimal union, it may be necessary to administer parenteral antibiotic therapy for as long as fixation hardware remains in place. Once fracture union is achieved, fixation hardware should be removed (if possible), with additional debridement if needed. (See 'Treatment' above.)

● Measures for prevention of osteomyelitis following open fracture include prompt debridement, surgical fixation (if needed), antibiotic therapy, and assessment regarding need for tetanus prophylaxis. (See 'Prevention' above.)

● Following open fracture, prompt administration of antibiotics (ideally within six hours) is warranted to reduce the risk of osteomyelitis (table 2). For patients with type I and type II fractures, antibiotic therapy should include activity against gram-positive organisms. For patients with type III fractures, antibiotic therapy should include activity against gram-positive and gram-negative organisms. The duration of antibiotic therapy depends on the classification of the fracture. (See 'Antibiotics after open fracture' above.)

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REFERENCES

1. Schmitt SK. Osteomyelitis. Infect Dis Clin North Am 2017; 31:325.

2. Hoff WS, Bonadies JA, Cachecho R, Dorlac WC. East Practice Management Guidelines Work Group: update to practice management guidelines for prophylactic antibiotic use in open fractures. J Trauma 2011; 70:751.

3. Pasquale M, Fabian TC. Practice management guidelines for trauma from the Eastern Association for the Surgery of Trauma. J Trauma 1998; 44:941.

4. Merritt K. Factors increasing the risk of infection in patients with open fractures. J Trauma 1988; https://www.uptodate.com/...yelitis-associated-with-open-fractures-in-adults/print?search=osteomyelitis&topicRef=7668&source=see_link[19.03.2020 15:31:01] Osteomyelitis associated with open fractures in adults - UpToDate

28:823.

5. DeLong WG Jr, Born CT, Wei SY, et al. Aggressive treatment of 119 open fracture wounds. J Trauma 1999; 46:1049.

6. Gross T, Kaim AH, Regazzoni P, Widmer AF. Current concepts in posttraumatic osteomyelitis: a diagnostic challenge with new imaging options. J Trauma 2002; 52:1210.

7. Patzakis MJ, Wilkins J. Factors influencing infection rate in open fracture wounds. Clin Orthop Relat Res 1989; :36.

8. Tsukayama DT. Pathophysiology of posttraumatic osteomyelitis. Clin Orthop Relat Res 1999; :22.

9. Lavery LA, Walker SC, Harkless LB, Felder-Johnson K. Infected puncture wounds in diabetic and nondiabetic adults. Diabetes Care 1995; 18:1588.

10. Court-Brown CM, Rimmer S, Prakash U, McQueen MM. The epidemiology of open long bone fractures. Injury 1998; 29:529.

11. Ketonis C, Dwyer J, Ilyas AM. Timing of Debridement and Infection Rates in Open Fractures of the Hand: A Systematic Review. Hand (N Y) 2017; 12:119.

12. Lew DP, Waldvogel FA. Osteomyelitis. Lancet 2004; 364:369.

13. Khatod M, Botte MJ, Hoyt DB, et al. Outcomes in open tibia fractures: relationship between delay in treatment and infection. J Trauma 2003; 55:949.

14. Mader JT, Ortiz M, Calhoun JH. Update on the diagnosis and management of osteomyelitis. Clin Podiatr Med Surg 1996; 13:701.

15. Trampuz A, Zimmerli W. Diagnosis and treatment of infections associated with fracture-fixation devices. Injury 2006; 37 Suppl 2:S59.

16. Haas DW, McAndrew MP. Bacterial osteomyelitis in adults: evolving considerations in diagnosis and treatment. Am J Med 1996; 101:550.

17. Karam GH, Ackley AM, Dismukes WE. Posttraumatic Aeromonas hydrophila osteomyelitis. Arch Intern Med 1983; 143:2073.

18. Lavery LA, Harkless LB, Felder-Johnson K, Mundine S. Bacterial pathogens in infected puncture wounds in adults with diabetes. J Foot Ankle Surg 1994; 33:91.

19. Kindsfater K, Jonassen EA. Osteomyelitis in grade II and III open tibia fractures with late debridement. J Orthop Trauma 1995; 9:121.

20. Lee J. Efficacy of cultures in the management of open fractures. Clin Orthop Relat Res 1997; :71.

21. Roesgen M, Hierholzer G, Hax PM. Post-traumatic osteomyelitis. Pathophysiology and management. Arch Orthop Trauma Surg 1989; 108:1.

22. Cierny G, Mader JT. Adult chronic osteomyelitis. Orthopedics 1984; 7:1557.

23. Böhm E, Josten C. What's new in exogenous osteomyelitis? Pathol Res Pract 1992; 188:254.

24. Meadows SE, Zuckerman JD, Koval KJ. Posttraumatic tibial osteomyelitis: diagnosis, classification, and treatment. Bull Hosp Jt Dis 1993; 52:11.

25. Anthony JP, Mathes SJ, Alpert BS. The muscle flap in the treatment of chronic lower extremity osteomyelitis: results in patients over 5 years after treatment. Plast Reconstr Surg 1991; 88:311.

26. May JW Jr, Jupiter JB, Gallico GG 3rd, et al. Treatment of chronic traumatic bone wounds. Microvascular free tissue transfer: a 13-year experience in 96 patients. Ann Surg 1991; 214:241.

27. Culliford AT 4th, Spector J, Blank A, et al. The fate of lower extremities with failed free flaps: a single institution's experience over 25 years. Ann Plast Surg 2007; 59:18.

28. Clifford RP, Beauchamp CG, Kellam JF, et al. Plate fixation of open fractures of the tibia. J Bone Joint Surg Br 1988; 70:644.

29. Clifford RP, Lyons TJ, Webb JK. Complications of external fixation of open fractures of the tibia. Injury 1987; 18:174.

30. Chapman MW. The role of intramedullary fixation in open fractures. Clin Orthop Relat Res 1986; :26.

31. Etter C, Burri C, Claes L, et al. Treatment by external fixation of open fractures associated with severe soft tissue damage of the leg. Biomechanical principles and clinical experience. Clin Orthop Relat Res 1983; :80.

32. Mehta D, Abdou S, Stranix JT, et al. Comparing Radiographic Progression of Bone Healing in Gustilo IIIB Open Tibia Fractures Treated With Muscle Versus Fasciocutaneous Flaps. J Orthop Trauma 2018; 32:381.

33. Prodromidis AD, Charalambous CP. The 6-Hour Rule for Surgical Debridement of Open Tibial Fractures: A Systematic Review and Meta-Analysis of Infection and Nonunion Rates. J Orthop Trauma 2016; 30:397.

34. Schenker ML, Yannascoli S, Baldwin KD, et al. Does timing to operative debridement affect infectious complications in open long-bone fractures? A systematic review. J Bone Joint Surg Am 2012; 94:1057.

35. Calhoun JH. Optimal timing of operative debridement: a known unknown: commentary on an article https://www.uptodate.com/...yelitis-associated-with-open-fractures-in-adults/print?search=osteomyelitis&topicRef=7668&source=see_link[19.03.2020 15:31:01] Osteomyelitis associated with open fractures in adults - UpToDate

by Mara L. Schenker, MD, et al.: “Does timing to operative debridement affect infectious complications in open long-bone fractures? A systematic review”. J Bone Joint Surg Am 2012; 94:e90.

36. Gosselin RA, Roberts I, Gillespie WJ. Antibiotics for preventing infection in open limb fractures. Cochrane Database Syst Rev 2004; :CD003764.

37. Rajasekaran S. Early versus delayed closure of open fractures. Injury 2007; 38:890.

38. Patzakis MJ, Wilkins J, Moore TM. Considerations in reducing the infection rate in open tibial fractures. Clin Orthop Relat Res 1983; :36.

39. Seligson D, Henry SL. Treatment of compound fractures. Am J Surg 1991; 161:693.

40. Patzakis MJ, Bains RS, Lee J, et al. Prospective, randomized, double-blind study comparing single- agent antibiotic therapy, ciprofloxacin, to combination antibiotic therapy in open fracture wounds. J Orthop Trauma 2000; 14:529.

41. Vasenius J, Tulikoura I, Vainionpää S, Rokkanen P. Clindamycin versus cloxacillin in the treatment of 240 open fractures. A randomized prospective study. Ann Chir Gynaecol 1998; 87:224.

42. Rodriguez L, Jung HS, Goulet JA, et al. Evidence-based protocol for prophylactic antibiotics in open fractures: improved antibiotic stewardship with no increase in infection rates. J Trauma Acute Care Surg 2014; 77:400.

43. Hauser CJ, Adams CA Jr, Eachempati SR, Council of the Surgical Infection Society. Surgical Infection Society guideline: prophylactic antibiotic use in open fractures: an evidence-based guideline. Surg Infect (Larchmt) 2006; 7:379.

44. Gillespie WJ, Walenkamp GH. Antibiotic prophylaxis for surgery for proximal femoral and other closed long bone fractures. Cochrane Database Syst Rev 2010; :CD000244.

45. Dellinger EP, Caplan ES, Weaver LD, et al. Duration of preventive antibiotic administration for open extremity fractures. Arch Surg 1988; 123:333.

46. Talan DA, Citron DM, Abrahamian FM, et al. Bacteriologic analysis of infected dog and cat bites. Emergency Medicine Animal Bite Infection Study Group. N Engl J Med 1999; 340:85.

47. Muguti GI, Dixon MS. Tetanus following human bite. Br J Plast Surg 1992; 45:614.

Topic 7659 Version 20.0

GRAPHICS

Gustilo-Anderson open fracture grading

Vascular injury Soft tissue Type Wound size Contamination Fracture requiring coverage repair

I Wound <1 cm Minimal Minimal No Adequate comminution; no periosteal stripping

II Wound >1 cm Moderate Moderate No Adequate comminution; minimal periosteal stripping

IIIA Any size Severe Severe No Adequate; may comminution or become segmental inadequate with fractures; debridements periosteal stripping

IIIB Any size Severe Severe No Inadequate comminution or (rotation flap or segmental free flap) fractures; periosteal stripping

IIIC Any size Severe Severe Yes Inadequate comminution or (rotation flap or segmental free flap) fractures; periosteal stripping

References: 1. Gustilo RB, Anderson JT. Prevention of infection in the treatment of one thousand and twenty-five open fractures of long bones: retrospective and prospective analyses. J Bone Joint Surg Am 1976; 58:453. 2. Gustilo RB, Gruninger RP, Davis T. Classification of type III (severe) open fractures relative to treatment and results. Orthopedics 1987; 10:1781.

Graphic 110486 Version 2.0

¶Δ ¶Δ

◊

Preventive antibiotic regimens for patients with open fractures

Presence of potential Absence of potential soil contamination Presence of water soil or water (in absence of water contamination contamination contamination)

Gustilo-Anderson fracture type I or II*

Preferred regimen Cefazolin 2 g IV every 8 Cefazolin 2 g IV every 8 No modification needed hours¶Δ hours¶Δ for fracture type I or II OR Ceftriaxone 2 g IV every 24 hours◊ PLUS

Metronidazole 500 mg IV every 8 hours

Alternative regimen for Vancomycin 20 mg/kg Clindamycin 900 mg IV No modification needed patients with beta-lactam loading dose, then 15 every 8 hours for fracture type I or II hypersensitivity mg/kg/dose IV every 12 hours

Gustilo-Anderson fracture type III§

Preferred regimen Ceftriaxone 2 g IV every Ceftriaxone 2 g IV every Fresh water 24 hours◊ 24 hours◊ contamination: OR OR Piperacillin-tazobactam 4.5 g IV every 6 Cefazolin 2 g IV every 8 Cefazolin 2 g IV every 8 hours◊¥ hours¶Δ hours¶Δ PLUS PLUS Sea water contamination: Piperacillin-tazobactam Gentamicin 5 mg/kg IV Gentamicin 5 mg/kg IV (as above)◊¥ every 24 hours every 24 hours PLUS PLUS Doxycycline 100 mg IV Metronidazole 500 mg IV or orally every 12 every 8 hours hours‡

Alternative regimen for Clindamycin 900 mg IV Clindamycin 900 mg IV Fresh water patients with beta-lactam every 8 hours every 8 hours contamination: hypersensitivity PLUS Imipenem 500 mg IV every 6 hours◊ Gentamicin 5 mg/kg IV OR every 24 hours Meropenem 1 g IV every 8 hours◊

Sea water contamination: Imipenem or meropenem (as above)◊ PLUS

Doxycycline 100 mg IV or orally every 12 hours‡

IV: intravenous. * For type I and II open fractures, prophylactic antibiotics may be discontinued 24 hours after wound closure. ¶ For patients >120 kg, cefazolin dosing consists of 3 g IV every 8 hours. Δ For patients at risk for methicillin-resistant Staphylococcus aureus (MRSA), gram-positive coverage should consist of vancomycin in place of cefazolin. ◊ For patients at risk for MRSA, vancomycin should be added to the regimen.

§ For Gustilo type III open fractures, prophylactic antibiotics may be discontinued after 72 hours or within a day after soft tissue injuries have been closed. ¥ For patients on vancomycin, imipenem or meropenem may be used in place of piperacillin-tazobactam, to minimize the likelihood of nephrotoxicity associated with coadministration of vancomycin and piperacillin-tazobactam. ‡ A fluoroquinolone (levofloxacin or ciprofloxacin) may be used as an alternative to doxycycline.

Graphic 126266 Version 1.0

Δ Δ ◊

§ §

Risk factors for methicillin-resistant Staphylococcus aureus (MRSA) infection

Health care-associated risk factors include:

Recent hospitalization

Residence in a long-term care facility

Recent surgery

Hemodialysis

Additional risk factors for MRSA infection include:

HIV infection

Injection drug use

Prior antibiotic use

Factors associated with MRSA outbreaks include:

Incarceration

Military service

Sharing sports equipment

Sharing needles, razors, or other sharp objects

Graphic 53504 Version 11.0

Δ Δ ◊

§ §

Wound management and tetanus prophylaxis

¶ Previous doses Clean and minor wound All other wounds

of tetanus Tetanus toxoid- Human tetanus Tetanus toxoid- Human tetanus toxoid* containing vaccineΔ immune globulin containing vaccineΔ immune globulin◊

<3 doses or unknown Yes§ No Yes§ Yes

≥3 doses Only if last dose given No Only if last dose given No ≥10 years ago ≥5 years ago¥

Appropriate tetanus prophylaxis should be administered as soon as possible following a wound but should be given even to patients who present late for medical attention. This is because the incubation period is quite variable; most cases occur within 8 days, but the incubation period can be as short as 3 days or as long as 21 days. For patients who have been vaccinated against tetanus previously but who are not up to date, there is likely to be little benefit in administering human tetanus immune globulin more than 1 week or so after the injury. However, for patients thought to be completely unvaccinated, human tetanus immune globulin should be given up to 21 days following the injury; Td or Tdap should be given concurrently to such patients.

DT: diphtheria-tetanus toxoids adsorbed; DTP/DTwP: diphtheria-tetanus whole-cell pertussis; DTaP: diphtheria-tetanus-acellular pertussis; Td: tetanus-diphtheria toxoids absorbed; Tdap: booster tetanus toxoid-reduced diphtheria toxoid-acellular pertussis; TT: tetanus toxoid. * Tetanus toxoid may have been administered as DT, DTP/DTwP (no longer available in the United States), DTaP, Td, Tdap, or TT (no longer available in the United States). ¶ Such as, but not limited to, wounds contaminated with dirt, feces, soil, or saliva; puncture wounds; avulsions; or wounds resulting from missiles, crushing, burns, or frostbite. Δ The preferred vaccine preparation depends upon the age and vaccination history of the patient: <7 years: DTaP. Underimmunized children ≥7 and <11 years who have not received Tdap previously: Tdap. Children who receive Tdap at age 7 through 9 years should receive another dose of Tdap at age 11 through 12 years. ≥11 years: A single dose of Tdap is preferred to Td for all individuals in this age group who have not previously received Tdap; otherwise, Td or Tdap can be administered without preference. Pregnant women should receive Tdap during each pregnancy. ◊ 250 units intramuscularly at a different site than tetanus toxoid; intravenous immune globulin should be administered if human tetanus immune globulin is not available. Persons with HIV infection or severe immunodeficiency who have contaminated wounds should also receive human tetanus immune globulin, regardless of their history of tetanus immunization. § The vaccine series should be continued through completion as necessary. ¥ Booster doses given more frequently than every 5 years are not needed and can increase adverse effects.

References:

1. Liang JL, Tiwari T, Moro P, et al. Prevention of Pertussis, Tetanus, and Diphtheria with Vaccines in the United States: Recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Recomm Rep 2018; 67:1. 2. Havers FP, Moro PL, Hunter P, et al. Use of tetanus toxoid, reduced diphtheria toxoid, and acellular pertussis vaccines: Updated recommendations of the Advisory Committee on Immunization Practices - United States, 2019. MMWR Morb Mortal Wkly Rep 2020; 69:77.

Graphic 61087 Version 34.0

Contributor Disclosures

Steven K Schmitt, MD, FIDSA Nothing to disclose Denis Spelman, MBBS, FRACP, FRCPA, MPH Nothing to disclose Elinor L Baron, MD, DTMH Nothing to disclose

Conflict of interest policy

Contributor Disclosures

Steven K Schmitt, MD, FIDSA Nothing to disclose Denis Spelman, MBBS, FRACP, FRCPA, MPH Nothing to disclose Elinor L Baron, MD, DTMH Nothing to disclose

Conflict of interest policy

https://www.uptodate.com/...yelitis-associated-with-open-fractures-in-adults/print?search=osteomyelitis&topicRef=7668&source=see_link[19.03.2020 15:31:01] Pelvic osteomyelitis and other infections of the bony pelvis in adults - UpToDate

Official reprint from UpToDate® www.uptodate.com ©2020 UpToDate, Inc. and/or its affiliates. All Rights Reserved. Print Options Print | Back Text References Graphics Pelvic osteomyelitis and other infections of the bony pelvisContributor in Disclosures adults

Author: Daniel J Sexton, MD Section Editor: Denis Spelman, MBBS, FRACP, FRCPA, MPH Deputy Editor: Elinor L Baron, MD, DTMH

All topics are updated as new evidence becomes available and our peer review process is complete.

Literature review current through: Feb 2020. | This topic last updated: Dec 17, 2019.

INTRODUCTION

Infections of the bones and joints of the pelvis may arise hematogenously, secondary to trauma or surgery via direct inoculation of pathogens into bone, or via contiguous spread of infection from soft tissues within or outside the bony walls of the pelvis. These infections may manifest as pelvic osteomyelitis or septic arthritis with contiguous spread to the adjacent bony margins.

Issues related to pelvic osteomyelitis and septic arthritis of the two principle joints of the pelvis (the pubic symphysis and sacroiliac joint) will be reviewed here.

General issues related to the pathogenesis and classification of osteomyelitis and the clinical features of other types of osteomyelitis are discussed separately. (See "Osteomyelitis in adults: Clinical manifestations and diagnosis" and "Pathogenesis of osteomyelitis" and "Osteomyelitis associated with open fractures in adults".)

Nonsuppurative processes involving the sacroiliac joint are discussed separately. (See "Clinical manifestations of axial spondyloarthritis (ankylosing spondylitis and nonradiographic axial spondyloarthritis) in adults" and "Clinical manifestations and diagnosis of arthritis associated with inflammatory bowel disease and other gastrointestinal diseases".)

Clinical manifestations of osteomyelitis and septic arthritis are discussed separately. (See "Osteomyelitis in adults: Clinical manifestations and diagnosis" and "Septic arthritis in adults".)

EPIDEMIOLOGY

Among the bones within the pelvis, ischium is the bone most commonly associated with osteomyelitis.

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Predisposing factors for pelvic osteomyelitis and pelvic septic arthritis include [1-6]:

● Bacteremia due to Staphylococcus aureus ● Bacteremia related to infection of intravascular catheters or other implanted devices ● Trauma (including athletic injuries, open fractures, and/or or instrumentation of the pelvic bones) ● Pressure ulcer(s) of the sacrum ● Obstetrical injuries or abortion ● Injection drug use ● Urogynecologic surgery, particularly involving procedures such as bladder suspension involving placement of bone anchors ● Other pelvic surgical procedures, including prostatectomy or transrectal prostate biopsy [7] ● Cardiac catheterization, especially when performed via the inguinal/femoral site ● Pelvic radiation, especially if complicated by osteoradionecrosis

These risk factors may predispose to infection at one or several bony sites in the pelvis. As an example, pressure ulcers predominantly predispose to infections of the sacrum and adjacent portions of the ilium. Injection drug use, cardiac catheterization, and bacteremia have a propensity to cause infections of the pubis. Pelvic or urologic surgery can result in infection of the pubis as well as other sites such as the sacroiliac joint.

Rarely, infection arises spontaneously without an identifiable cause; such cases are likely complications of bacteremia that developed from an unrecognized site or event [8]. In some circumstances, it may be impossible to determine if trauma alone or trauma plus an incidental bacteremia led to the subsequent infection.

ANATOMY

The pelvic walls contain bone, ligaments, and muscles (figure 1). The bony pelvis consists of two hip bones (os coxae) that are joined in front by the pubic symphysis. The os coxae articulate posteriorly with the sacrum. The hip (coxal) bones consist of the ilium, the ischium, and the pubis. Both the pubis and ischium are further divided into their respective bodies and rami. The os coxae have been likened to a propeller with two oppositely bent blades with a central shaft (the acetabulum).

The pelvis contains two joints: the sacroiliac joint and the symphysis pubis. The sacroiliac joint is part synovial (one-third) and part cartilage (two-thirds); the symphysis pubis consists of cartilaginous layers on either side of an interpubic disk consisting of fibrocartilage. Fibrous ligaments such as the iliolumbar ligament further stabilize the bony pelvis.

The microanatomy of the blood supply of the symphysis pubis is controversial; there is evidence that blood vessels penetrate the dense connective tissue in rim of the fibrocartilage as well as the contiguous bones of the os coxae [9].

MICROBIOLOGY

Pathogens responsible for pelvic osteomyelitis vary depending on the pathogenesis of the infection. Hematogenous infections are commonly due to S. aureus (including methicillin-resistant S. aureus) [10], but almost any pathogen capable of causing primary or secondary bacteremia can cause a hematogenous infection in the bony pelvis [11]. Intravenous drug abusers who develop pubic osteomyelitis or septic sacroiliitis appear to have a higher propensity to have Pseudomonas aeruginosa as a causative pathogen [12]. Postoperative pelvic osteomyelitis infections and infections secondary to decubitus ulcers are commonly mixed infections due to bowel or perineal flora [13].

CLINICAL MANIFESTATIONS

Overview — Patients with acute sacroiliitis or pubic osteomyelitis may have fever and severe pain; however, many bony infections of the pelvis present subacutely with or without associated fever. Physical examination may be useful when predisposing causes such as pressure ulcers are present and patients have localized pain and tenderness over discrete sites such as the symphysis pubis or sacroiliac joints and inguinal region. In other cases, pain may be poorly localized or accompanied by other confusing symptoms such as antalgic gait, limp, hip or buttock pain, or inability to bear weight [14]. In patients with spinal cord injury, pain may be absent.

Several clinical aspects of pelvic osteomyelitis and septic arthritis warrant special emphasis [11,13,15- 18]:

● There may be a long interval between a precipitating cause (such as trauma or surgery) and the onset of pelvic osteomyelitis, and fever may be absent. These factors may contribute to diagnostic delay.

● Patients with pubic osteomyelitis initially develop an infection of the pubic symphysis that later produces osteomyelitis in adjacent pubic rami. Such patients characteristically have severe pelvic pain associated with point tenderness overlying the symphysis pubis. They usually also have difficulty walking and manifest a characteristic wide-based waddling gait.

● Patients with pyogenic sacroiliitis and secondary pelvic osteomyelitis may have vague poorly localized pain or pain in the buttock or hip. However, focal tenderness on exam is usually present with pressure or percussion over the sacroiliac region [19].

● Patients with pelvic osteomyelitis may develop abscesses in soft tissues adjacent to the bony pelvis or infection may dissect into areas that are quite distant from the site of bony involvement. For example, pubic osteomyelitis can lead to bilateral abscesses in the adductor muscles of the thigh [17].

Osteitis pubis — Osteitis pubis is an idiopathic postoperative complication of suprapubic cystotomy.

Patients with this condition have bony destruction of the margins of the symphysis pubis, severe pelvic pain, and a characteristic wide-based waddling gait [20]. Osteitis pubis has been recognized as a complication of a wide range of urologic and gynecologic surgical procedures. It has been described in association with pregnancy, hernia repairs, pyelonephritis, and presumed trauma in athletes [10,13]. Sinus tracts, a characteristic manifestation of osteomyelitis, have been described in some patients. Fever is usually absent.

The pathogenesis of osteitis pubis is uncertain. Possible etiologies include infection, mechanical trauma to the symphysis, local vascular damage, or reflex sympathetic dystrophy. Some experts believe that all cases of osteitis pubis are secondary to infection (eg, that osteitis pubis is synonymous with pubic osteomyelitis) [13]. Others believe that pubic osteomyelitis and osteitis pubis are separate conditions (ie, that osteitis pubis is not an infectious disease) [21]. Even though this controversy remains unresolved, the possibility of infection (osteomyelitis) should be carefully assessed in every patient with presumed osteitis pubis. (See "Osteitis pubis".)

Sacral osteomyelitis — Most commonly, sacral osteomyelitis arises from contiguous spread of infection from deep (stage IV) pressure ulcers. It may also arise as a complication of open or laparoscopic pelvic surgery [22,23], following pelvic radiation, spinal or anal surgery, after penetrating trauma such as a gunshot wound, or in the setting of sacral fracture or epidural anesthesia [24].

DIAGNOSIS

Culture and/or histopathologic examination of a bone biopsy are required in order to make a definitive diagnosis of osteomyelitis. In general, rates of culture positivity are higher when cultures are obtained at the time of surgical debridement. The utility of percutaneous bone biopsy in the setting of pelvic osteomyelitis is controversial; some centers report a low yield of cultures from such procedures. As an example, in one report including 35 biopsies of the pelvis, a pathogen was identified in only 17 percent of cases [25].

Compatible symptoms in the setting of relevant risk factors, together with positive blood cultures and radiographic evidence of osteomyelitis, may also be diagnostic. Aspiration and cultures of pus obtained from abscesses that are contiguous to bony pelvic abnormalities may supplant the need for bone biopsy in some cases. (See "Osteomyelitis in adults: Clinical manifestations and diagnosis", section on 'Diagnosis'.)

White blood counts, erythrocyte sedimentation rate, and measurement of C-reactive protein levels may provide clues to the presence of an infectious process in the bony pelvis. However, these tests lack specificity in distinguishing bony infection from other noninfectious conditions such as seronegative spondyloarthropathies.

Plain radiography is not sensitive for detecting osteomyelitis, although it may be useful to exclude other causes of pain such as tumor or fractures. Computed tomography (CT) is more sensitive than plain

radiography in detecting pelvic osteomyelitis, pyogenic sacroiliitis, or early pubic osteomyelitis but is less sensitive than magnetic resonance imaging (MRI). CT or ultrasound may be useful in detecting soft tissue swelling and abscess formation in contiguous soft tissues, particularly when aspiration or drainage procedures are planned. (See "Approach to imaging modalities in the setting of suspected nonvertebral osteomyelitis".)

MRI is the most sensitive radiographic modality for detection of pelvic osteomyelitis. Marrow abnormalities typical of osteomyelitis may be detected by MRI before lytic or other typical changes of osteomyelitis appear. (See "Approach to imaging modalities in the setting of suspected nonvertebral osteomyelitis".)

DIFFERENTIAL DIAGNOSIS

Pelvic bone and joint infections can be difficult to distinguish from other mimics. For example, pubic osteomyelitis may rarely be confused with spermatic cord torsion [26]. Chronic recurrent multifocal osteomyelitis, a rare condition of unknown etiology that most often affects long bones, can affect the bony pelvis in rare cases, particularly in children and adolescents [27]. Postradiation changes, healing fractures, and a variety of pathological problems involving the hip can also be mimics of pelvic osteomyelitis. Obturator pyomyositis can rarely mimic pelvic osteomyelitis as well as lead to secondary osteomyelitis of the ischio-pubic bones [28,29].

TREATMENT

Treatment of pelvic osteomyelitis consists of debridement of infected or necrotic tissues, in conjunction with antimicrobial therapy directed at the causative pathogens. (See "Osteomyelitis in adults: Clinical manifestations and diagnosis" and "Osteomyelitis associated with open fractures in adults" and "Osteomyelitis in adults: Treatment".)

In general, pelvic osteomyelitis associated with sacral decubitus ulcer(s) requires surgical debridement for cure [6]. Often, tissue reconstruction is required following debridement and antimicrobial therapy [30,31]. In some circumstances, definitive debridement of advanced osteomyelitis associated with adjacent sacral decubitus ulcers is not be possible. For some cases, hemicorporectomy has been performed; morbidity and mortality in such cases is high [32].

For patients with osteomyelitis involving the ilium, acetabulum, or ischium, thorough debridement may be difficult because of the proximity of overlying or adjacent structures such as the sacral plexus, and/or because of difficult access for areas deep within the pelvis. In addition, debridement of the symphysis pubis may be associated with subsequent instability and gait problems.

For cases in which definitive debridement is not feasible, a long course of intravenous antibiotics (eg, six to eight weeks) may be sufficient for cure [19]. Successful management of pubic osteomyelitis have been

managed with antimicrobial therapy without extensive debridement (after needle biopsy demonstrated a causative pathogen) has been described [13,33,34].

Selection of antibiotic therapy should be guided by bone cultures obtained via open biopsy or aspiration. For cases in which such microbiology data is not available, empiric antibiotic therapy should include activity against staphylococci, gram-negative bacilli, and anaerobes. Reasonable regimens include vancomycin in combination with a third- or fourth-generation cephalosporin (such as ceftriaxone, ceftazidime, or cefepime) and metronidazole. An alternative regimen consists of vancomycin in combination with a carbapenem.

The optimal duration of antibiotic therapy for treatment of pelvic osteomyelitis is uncertain. Most experts favor continuing antimicrobial therapy at least until debrided bone has been covered by vascularized soft tissue, which is usually at least six weeks from the last debridement.

OUTCOMES

Risk factors for treatment failure include fistula, malignancy, polymicrobial infection, and resistant organisms [35]. In one review including 61 patients with chronic osteomyelitis who underwent surgical debridement, the recurrence rate was 11.5 percent [31]. In another retrospective cohort study including 61 patients with pelvic osteomyelitis associated with pressure ulcer who underwent debridement and flap coverage with antimicrobial therapy for 20 weeks, the rate of treatment failure was 23 percent [36].

SOCIETY GUIDELINE LINKS

SUMMARY

● Pelvic osteomyelitis may arise hematogenously, secondary to trauma or surgery via direct inoculation of pathogens into bone, or via contiguous spread of infection from soft tissues within or outside the bony walls of the pelvis. (See 'Introduction' above.)

● Predisposing factors for pelvic osteomyelitis include bacteremia related to infection of implanted devices, trauma, pressure ulcers, pelvic or urologic surgery, obstetrical procedures, and intravenous drug abuse. (See 'Epidemiology' above.)

● There may be a long interval between a precipitating cause (such as trauma or surgery) and the onset of pelvic osteomyelitis, and fever may be absent. (See 'Clinical manifestations' above.)

● Osteitis pubis consists of bony destruction of the margins of the symphysis pubis, severe pelvic pain, and a characteristic wide-based waddling gait. Fever is usually absent. Osteitis pubis may occur as a result of infection or noninfectious causes. (See 'Osteitis pubis' above.)

● Culture and/or histopathological examination of a bone biopsy are required in order to make a definitive diagnosis of osteomyelitis. Magnetic resonance imaging (MRI) is the most sensitive radiographic modality for detection of pelvic osteomyelitis. (See 'Treatment' above.)

● Treatment of pelvic osteomyelitis consists of debridement of infected or necrotic tissues and a long course of antimicrobial therapy directed at the causative pathogens. In some cases, thorough debridement may be anatomically difficult and/or may result in instability and secondary gait problems. In such cases, a long course of antimicrobial therapy without extensive debridement may be sufficient. Pelvic osteomyelitis due to sacral decubitus ulcer generally requires surgical debridement for cure. (See 'Treatment' above.)

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REFERENCES

1. Ukwu HN, Graham BS, Latham RH. Acute pubic osteomyelitis in athletes. Clin Infect Dis 1992; 15:636.

2. Kaplon DM, Iannotti H. Prostatic capsular perforation with extravasation resulting in pubic osteomyelitis: a rare complication of KTP laser prostatectomy. J Endourol 2008; 22:2705.

3. Graham CW, Dmochowski RR, Faerber GJ, et al. Pubic osteomyelitis following bladder neck surgery using bone anchors: a report of 9 cases. J Urol 2002; 168:2055.

4. Dinan JJ. TWO CASES OF PRIMARY OSTEOMYELITIS OF THE PUBIC BONE. Can Med Assoc J 1939; 41:436.

5. Guthrie R, Monk J. Osteomyelitis of the symphysis pubis: a complication of cardiac catheterisation. Br J Clin Pract 1989; 43:383.

6. Bodavula P, Liang SY, Wu J, et al. Pressure Ulcer-Related Pelvic Osteomyelitis: A Neglected Disease? Open Forum Infect Dis 2015; 2:ofv112.

7. Albers LF, Korving JC, van Elzakker EPM, Roshani H. Osteomyelitis of the Pubic Symphysis After Transrectal Biopsies of the Prostate. Urology 2018; 121:29.

8. Dourakis SP, Alexopoulou A, Metallinos G, et al. Pubic osteomyelitis due to Klebsiella pneumoniae in a patient with diabetes mellitus. Am J Med Sci 2006; 331:322.

9. da Rocha RC, Chopard RP. Nutrition pathways to the symphysis pubis. J Anat 2004; 204:209.

10. Cosma S, Borella F, Carosso A, et al. Osteomyelitis of the pubic symphysis caused by methicillin- resistant Staphylococcus aureus after vaginal delivery: a case report and literature review. BMC Infect Dis 2019; 19:952.

11. Highland TR, LaMont RL. Osteomyelitis of the pelvis in children. J Bone Joint Surg Am 1983; 65:230.

12. Ross JJ, Hu LT. Septic arthritis of the pubic symphysis: review of 100 cases. Medicine (Baltimore) 2003; 82:340.

13. Sexton DJ, Heskestad L, Lambeth WR, et al. Postoperative pubic osteomyelitis misdiagnosed as osteitis pubis: report of four cases and review. Clin Infect Dis 1993; 17:695.

14. Deore S, Bansal M. Pelvic Osteomyelitis in a Child - A Diagnostic Dilemma. J Orthop Case Rep 2018; 8:86.

15. Takemoto RC, Strongwater AM. Pelvic osteomyelitis mimicking septic hip arthritis: a case report. J Pediatr Orthop B 2009; 18:248.

16. Beaupré A, Carroll N. The three syndromes of iliac osteomyelitis in children. J Bone Joint Surg Am 1979; 61:1087.

17. Yoshida S, Nakagomi K, Goto S. Abscess formation in the prevesical space and bilateral thigh muscles secondary to osteomyelitis of the pubis--basis of the anatomy between the prevesical space and femoral sheath. Scand J Urol Nephrol 2004; 38:440.

18. del Busto R, Quinn EL, Fisher EJ, Madhavan T. Osteomyelitis of the pubis. Report of seven cases. JAMA 1982; 248:1498.

19. Bindal M, Krabak B. Acute bacterial sacroiliitis in an adult: a case report and review of the literature. Arch Phys Med Rehabil 2007; 88:1357.

20. Beer E. Periostitis and ostitis of the symphysis and rami of the pubis following suprapubic cystotomies. Int J Med Surg 1924; 237:233.

21. Rosenthal RE, Spickard WA, Markham RD, Rhamy RK. Osteomyelitis of the symphysis pubis: a separate disease from osteitis pubis. Report of three cases and review of the literature. J Bone Joint Surg Am 1982; 64:123.

22. Apostolis CA, Heiselman C. Sacral osteomyelitis after laparoscopic sacral colpopexy performed after a recent dental extraction: a case report. Female Pelvic Med Reconstr Surg 2014; 20:e5.

23. Iavazzo C, Gkegkes ID. Osteomyelitis after robotically assisted laparoscopic sacral colpopexy. Acta

Inform Med 2013; 21:143.

24. Wittum S, Hofer CK, Rölli U, et al. Sacral osteomyelitis after single-shot epidural anesthesia via the caudal approach in a child. Anesthesiology 2003; 99:503.

25. Said N, Chalian M, Fox MG, Nacey NC. Percutaneous image-guided bone biopsy of osteomyelitis in the foot and pelvis has a low impact on guiding antibiotics management: a retrospective analysis of 60 bone biopsies. Skeletal Radiol 2019; 48:1385.

26. Charles P, Ackermann F, Brousse C, et al. [Spontaneous streptococcal arthritis of the pubic symphysis]. Rev Med Interne 2011; 32:e88.

27. Zellali K, Benard E, Smokvina E, et al. Multifocal pelvic osteomyelitis in a child associated with cat- scratch disease: a case report and review of the literature. Paediatr Int Child Health 2019; 39:290.

28. de Bodman C, Ceroni D, Dufour J, et al. Obturator externus abscess in a 9-year-old child: A case report and literature review. Medicine (Baltimore) 2017; 96:e6203.

29. Kiran M, Mohamed S, Newton A, et al. Pelvic pyomyositis in children: changing trends in occurrence and management. Int Orthop 2018; 42:1143.

30. Rennert R, Golinko M, Yan A, et al. Developing and evaluating outcomes of an evidence-based protocol for the treatment of osteomyelitis in Stage IV pressure ulcers: a literature and wound electronic medical record database review. Ostomy Wound Manage 2009; 55:42.

31. Dudareva M, Ferguson J, Riley N, et al. Osteomyelitis of the Pelvic Bones: A Multidisciplinary Approach to Treatment. J Bone Jt Infect 2017; 2:184.

32. Janis JE, Ahmad J, Lemmon JA, et al. A 25-year experience with hemicorporectomy for terminal pelvic osteomyelitis. Plast Reconstr Surg 2009; 124:1165.

33. COVENTRY MB, MITCHELL WC. Osteitis pubis: observations based on a study of 45 patients. JAMA 1961; 178:898.

34. Choi H, McCartney M, Best TM. Treatment of osteitis pubis and osteomyelitis of the pubic symphysis in athletes: a systematic review. Br J Sports Med 2011; 45:57.

35. Becker A, Triffault-Fillit C, Valour F, et al. Pubic osteomyelitis: Epidemiology and factors associated with treatment failure. Med Mal Infect 2019.

36. Andrianasolo J, Ferry T, Boucher F, et al. Pressure ulcer-related pelvic osteomyelitis: evaluation of a two-stage surgical strategy (debridement, negative pressure therapy and flap coverage) with prolonged antimicrobial therapy. BMC Infect Dis 2018; 18:166.

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GRAPHICS

Anatomy of human pelvic bone

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Contributor Disclosures

Daniel J Sexton, MD Grant/Research/Clinical Trial Support: Centers for Disease Control and Prevention; National Institutes of Health [Healthcare epidemiology]. Consultant/Advisory Boards: Magnolia Medical Technologies [Medical diagnostics]; National Football League [Infection prevention]; Johnson & Johnson [Mesh-related infections]. Equity Ownership/Stock Options: Magnolia Medical Technologies [Medical diagnostics]. Denis Spelman, MBBS, FRACP, FRCPA, MPH Nothing to disclose Elinor L Baron, MD, DTMH Nothing to disclose

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https://www.uptodate.com/...t?search=osteomyelitis&source=search_result&selectedTitle=10~150&usage_type=default&display_rank=10[19.03.2020 15:31:17] Vertebral osteomyelitis and discitis in adults - UpToDate

Official reprint from UpToDate® www.uptodate.com ©2020 UpToDate, Inc. and/or its affiliates. All Rights Reserved. Print Options Print | Back Text References Graphics Vertebral osteomyelitis and discitis in adults Contributor Disclosures Authors: Malcolm McDonald, PhD, FRACP, FRCPA, Trisha Peel, MD, MBBS Section Editor: Denis Spelman, MBBS, FRACP, FRCPA, MPH Deputy Editor: Elinor L Baron, MD, DTMH

All topics are updated as new evidence becomes available and our peer review process is complete.

Literature review current through: Feb 2020. | This topic last updated: Dec 17, 2019.

INTRODUCTION

Vertebral osteomyelitis most often occurs as a result of hematogenous seeding of one or more vertebral bodies from a distant focus [1]. Infection may also involve the adjacent intervertebral disc space, which has no direct blood supply in adults. Infection can also arise following surgery or injection of the disc space or via contiguous spread from adjacent soft tissue infection.

Vertebral osteomyelitis and discitis may occur together or independently. The diagnosis and management of these two entities are similar in most patients. The term pyogenic spondylitis refers to either vertebral osteomyelitis or discitis.

Issues related to vertebral osteomyelitis will be reviewed here. Issues related to other forms of hematogenous osteomyelitis in adults are discussed separately. (See "Osteomyelitis in adults: Clinical manifestations and diagnosis", section on 'Hematogenous osteomyelitis'.)

Issues related to spinal epidural abscess and tuberculous spinal infections are discussed separately. (See "Spinal epidural abscess" and "Skeletal tuberculosis".)

EPIDEMIOLOGY

Vertebral osteomyelitis is primarily a disease of adults; most cases occur in patients >50 years old [2]. The incidence increases with age. Men are affected approximately twice as often as women in most case series; the reason for this is not fully understood. Risk factors for vertebral osteomyelitis include injection drug use, infective endocarditis, degenerative spine disease, prior spinal surgery, diabetes mellitus, corticosteroid therapy, or other immunocompromised state. (See 'Pathogenesis' below.)

The annual incidence of hospitalization for vertebral osteomyelitis in the United States between 1998 and 2013 rose from 2.9 to 5.4 per 100,000, with lengthy hospital stays and substantial, long-term burden for patients and the health system [3]. Reasons for the increase in incidence include [1]: https://www.uptodate.com/...rint?search=osteomyelitis&source=search_result&selectedTitle=8~150&usage_type=default&display_rank=8[19.03.2020 15:30:43] Vertebral osteomyelitis and discitis in adults - UpToDate

● Increasing rates of bacteremia due to intravascular devices and other forms of instrumentation; an increasing proportion of vertebral osteomyelitis is health care related and/or post-procedural (up to one-third of new cases) [4,5].

● Increasing age of the population

● Increasing number of patients on renal replacement therapy

● Increasing number of patients on immunosuppressive medications

PATHOGENESIS

Mechanisms of infection — Bacteria can reach the bones of the spine by three basic routes (see "Pathogenesis of osteomyelitis"):

● Hematogenous spread from a distant site or focus of infection ● Direct inoculation from trauma, invasive spinal diagnostic procedures, or spinal surgery (image 1) ● Contiguous spread from adjacent soft tissue infection

Potential sources of hematogenous or contiguous spread of infection include the genitourinary tract, skin and soft tissue (eg, injection drug use), respiratory tract, infected intravascular devices, postoperative wound infection, infective endocarditis, and dental infection. In many cases, the primary site of infection cannot be identified [6]. Less common causes include infected native or prosthetic heart valve infections, direct spread from a ruptured esophagus, diverticular or renal abscesses, and infected aortic lesions (image 2) [7].

Vertebral osteomyelitis has been reported as a complication of lumbar puncture, myelography, translumbar aortography, chemonucleolysis, discography, facet joint corticosteroid injection [8], epidural catheter placement, and epidural corticosteroid injection [9].

Hematogenous spread — Hematogenous spread is by far the most common cause of vertebral osteomyelitis. Adult vertebral bone has abundant, highly vascular marrow with a sluggish but high- volume blood flow via nutrient vessels of the posterior spinal artery. With aging, these vessels progressively develop a characteristic "corkscrew" anatomy that may predispose to bacterial hematogenous seeding.

Bloodborne organisms that transit the vertebral marrow cavity can produce a spontaneous local suppurative infection. Initiation of infection may be facilitated by recent or prior bone trauma with disruption of normal architecture.

Segmental arteries supplying the vertebrae usually bifurcate to supply two adjacent end plates of contiguous vertebrae. Thus, hematogenous vertebral osteomyelitis often causes bone destruction in two adjacent vertebral bodies and usually destroys their intervertebral disc. The lumbar vertebral bodies are

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most often involved, followed by thoracic and, less commonly, cervical vertebrae. Hematogenous sacral osteomyelitis is rare.

Skip lesions with more than one level of spinal infection occur in less than 5 percent of reported cases. Noncontiguous epidural abscesses appear to be more common (10 percent) [10].

It was previously postulated that spread of infection might occur via vertebral veins known as Batson plexus [11,12]; this theory has been discounted.

Contiguous spread — Contiguous spread of infection may occur from tissues adjacent to the spine, such as the aorta, esophagus, or bowel. In such cases, extension of infection is facilitated by absence of a circumferential cartilage plate or a layer of subchondral compact bone [13].

Sacral osteomyelitis most commonly occurs as a complication of a sacral pressure ulcer, although it can follow pelvic infection, trauma, and/or surgery. Typically, it is polymicrobial and restricted to cortical bone [14,15]. (See "Infectious complications of pressure-induced skin and soft tissue injury", section on 'Osteomyelitis'.)

Extension of infection — Extension of infection posteriorly can lead to epidural abscess, subdural abscess, or meningitis (image 1). Extension of infection anteriorly or laterally can lead to paravertebral, retropharyngeal, mediastinal, subphrenic, retroperitoneal, or psoas abscess (image 3 and table 1). Development of epidural or paravertebral abscess is more common in the setting of gram-positive infection than gram-negative infection [16]. In addition, thoracic vertebral infections can extend into the pleural space to produce an empyema [17].

Infection can occur in spinal elements other than the vertebral bodies, including the posterior spinous processes, the facet joints, the pedicles, and, rarely, the odontoid process [18].

MICROBIOLOGY

Most patients have monomicrobial infection. The most common cause of vertebral osteomyelitis is Staphylococcus aureus, accounting for more than 50 percent of cases in most series from developed countries. The relative importance of methicillin-resistant S. aureus as a cause of vertebral osteomyelitis has increased as the community and hospital proportion of S. aureus strains that are methicillin resistant have increased.

Other causes of vertebral osteomyelitis include [19,20]:

● Enteric gram-negative bacilli, particularly following urinary tract instrumentation

● Nonpyogenic streptococci, including viridans group, milleri group, Streptococcus bovis, and enterococci [21,22]

● Pyogenic streptococci, including groups B and C/G, especially in patients with diabetes mellitus (see

"Group B Streptococcus: Virulence factors and pathogenic mechanisms" and "Group C and group G streptococcal infection")

● Pseudomonas aeruginosa, coagulase-negative staphylococci, and Candida spp, especially in association with intravascular access, sepsis, or injection drug use [20,23] (see "Candida osteoarticular infections")

● Tuberculous infection (see "Skeletal tuberculosis")

● Brucellosis, especially Brucella melitensis in North Africa, the Mediterranean rim, and the Middle East [24] (see "Brucellosis: Epidemiology, microbiology, clinical manifestations, and diagnosis")

Geography also influences the organisms associated with vertebral osteomyelitis. Burkholderia pseudomallei (melioidosis) is a potential pathogen in patients from periequatorial regions, and Salmonella and Entamoeba histolytica are occasional causes in sub-Saharan Africa or South America.

CLINICAL FEATURES

Symptoms and signs — The major clinical manifestation of vertebral osteomyelitis is pain; pain is typically localized to the infected disc space area and is exacerbated by physical activity or percussion to the affected area. Pain may radiate to the abdomen, leg, scrotum, groin, or perineum.

Spinal pain usually begins insidiously and progressively worsens over several weeks to months. In one series of 64 patients with hematogenous vertebral osteomyelitis, the mean duration of symptoms was 48±40 days [20]. The pain is often worse at night; initially, it may be relieved by bed rest. Pain may be absent in patients with paraplegia.

Patients whose infections extend posteriorly into the epidural space may present with clinical features of an epidural abscess; this often consists of focal and severe back pain, followed by radiculopathy, then motor weakness and sensory changes (including loss of bowel and bladder control and loss of perineal sensation), and eventual paralysis. The risk of severe neurologic deficit is increased in the presence of epidural abscess, especially with thoracic or cervical spinal involvement [25]. (See "Spinal epidural abscess".)

Fever is an inconsistent finding. One review noted a frequency of 52 percent [2]; lower rates have been noted in other studies [26].

Local tenderness to gentle spinal percussion is the most useful clinical sign but is not specific. Back pain is often accompanied by reduced mobility and/or spasm of nearby muscles. Rarely, a mass or spinal deformity may be visible.

The physical examination should include palpation for a distended bladder (may reflect spinal cord compression), evaluation for signs of psoas abscess (eg, flank pain and pain with hip extension), and a careful neurologic assessment of the lower limbs. https://www.uptodate.com/...rint?search=osteomyelitis&source=search_result&selectedTitle=8~150&usage_type=default&display_rank=8[19.03.2020 15:30:43] Vertebral osteomyelitis and discitis in adults - UpToDate

A careful general examination is essential to evaluate for potential sources of hematogenous spread; these include injection sites and recent skin or soft tissue infection.

Laboratory findings — The leukocyte count may be elevated or normal. Elevations in the erythrocyte sedimentation rate (ESR), which can exceed 100 mm/h, and C-reactive protein (CRP) are observed in more than 80 percent of patients [27-29].

If elevated, the ESR and CRP are useful for following the efficacy of therapy. (See 'Clinical and laboratory monitoring' below.)

DIAGNOSIS

Vertebral osteomyelitis should be suspected in the setting of new or worsening back or neck pain, especially with fever, and/or presence of bloodstream infection or infective endocarditis (IE) [1]. It should also be suspected in patients with fever and new peripheral neurologic symptoms (with or without back pain) and in patients with new back or neck pain following a recent episode of bacteremia (especially with S. aureus) or fungemia.

The diagnosis of vertebral osteomyelitis or discitis is established based on positive culture obtained from computed tomography (CT)-guided biopsy of the involved vertebra(e) and/or disc space. The diagnosis may be inferred in the setting of clinical and radiographic findings typical of vertebral osteomyelitis and positive blood cultures with a likely pathogen such as S. aureus. Similarly, the diagnosis may be inferred in the setting of histopathologic findings consistent with infection in the absence of positive culture data, particularly in the setting of recent antibiotic administration. For circumstances in which there are no positive microbiologic cultures or Gram stains and a biopsy cannot be performed, the diagnosis may be inferred in the setting of suggestive clinical and typical radiographic findings and persistently elevated inflammatory markers.

Back pain due to vertebral osteomyelitis may respond initially to bed rest and conservative measures, leading to the erroneous conclusion of minor trauma, muscle strain, or other noninfectious cause. In addition, a history of degenerative spinal disease or recent trauma sometimes obscures or delays the true diagnosis. In such cases a sedimentation rate (or serial sedimentation rates) can be useful; a normal result is reassuring.

Suggested clinical approach — Initial evaluation of patients with suspected vertebral osteomyelitis begins with careful history and physical examination; patients should have a thorough neurologic exam and should be questioned about predisposing factors including presence of indwelling devices, recent instrumentation, and injection drug use. Initial diagnostic tests include inflammatory markers (erythrocyte sedimentation rate [ESR] and C-reactive protein [CRP]) and cultures (blood and urine), followed by spinal imaging (magnetic resonance imaging [MRI] preferred if available) (algorithm 1). (See 'Radiographic imaging' below.)

Evaluation for surgery is warranted for patients with neurologic deficits, radiographic evidence of epidural or paravertebral abscess, and/or cord compression (threatened or actual). Ongoing monitoring for emergence or progression of neurologic signs is essential. In one case-control study including 97 patients with vertebral osteomyelitis and severe neurologic deficit, risk factors for neurologic deficit included epidural abscess and thoracic vertebral involvement [25]. (See 'Surgery' below.)

In the absence of the above conditions warranting surgical intervention, patients with radiographic evidence of vertebral osteomyelitis should undergo CT-guided needle biopsy of the affected bone and aspiration of abscess if present [19]. The specimens should be sent for bacterial (aerobic and anaerobic), fungal, and mycobacterial culture as well as histologic examination.

If possible, antimicrobial therapy should be withheld until a microbiologic diagnosis is confirmed. Clinical exceptions include neurologic compromise and sepsis; in these circumstances, empiric antibiotic therapy is warranted [1]. (See 'Antimicrobial therapy' below.)

A needle biopsy may not be necessary in patients with clinical and radiographic findings typical of vertebral osteomyelitis and positive blood cultures with a likely pathogen (such as S. aureus, Staphylococcus lugdunensis) or in patients with positive serology for Brucella (which is warranted for patients with relevant risk factors) [1]. Similarly, a positive blood culture due to a gram-negative enteric rod, P. aeruginosa, or other invasive pathogen is usually good evidence that the same pathogen is also the cause of the spinal infection. However, blood culture isolates do not always correlate with culture results from needle biopsy; therefore, needle biopsy is warranted for cases in which an alternate source for the bacteremia is present or strongly suspected [23]. (See "Brucellosis: Epidemiology, microbiology, clinical manifestations, and diagnosis".)

If cultures of blood and the needle aspirate are negative and the clinical suspicion for vertebral osteomyelitis remains high (on the basis of clinical and radiographic findings), we advocate performing a second biopsy. In one retrospective study including 136 patients with vertebral osteomyelitis in the absence of bacteremia, first biopsy was positive in 43 percent of cases and a second biopsy in 40 percent of cases; when combined with blood culture results, this approach led to microbiological diagnosis in nearly 75 percent of cases [30]. Performing blood cultures immediately following biopsy does not appear to add any benefit.

If repeat biopsy specimens and initial blood cultures are nondiagnostic, we usually initiate empiric therapy as discussed below. If such therapy does not result in objective clinical improvement in three to four weeks, a third percutaneous needle biopsy or an open surgical biopsy should be performed. Some suggest that, if the first set of cultures is negative, open biopsy be pursued before starting antibiotic therapy [19]. (See 'Antimicrobial therapy' below.)

The individual clinical approach must include consideration of the location of the infection, the underlying health of the patient, and the experience of the local surgeons.

Diagnostic tools — Diagnostic tools for vertebral osteomyelitis include cultures (blood and urine),

imaging studies, and biopsy.

Microbiology cultures — Blood and urine cultures should be obtained in all patients with suspected vertebral osteomyelitis; they are positive in up to 50 of cases [20,23]. (See 'Suggested clinical approach' above.)

In the setting of positive blood cultures for gram-positive organisms, evaluation for concurrent IE is warranted in patients with underlying valvular disease and/or new-onset heart failure. (See 'Evaluation for endocarditis' below.)

Radiographic imaging — MRI is the most sensitive radiographic technique for diagnosis of vertebral osteomyelitis and epidural abscess [31]. CT is a reasonable alternative imaging modality when MRI is not available. If neither CT nor MRI is available, plain films should be pursued; however, plain films typically demonstrate radiographic findings only after the disease has become advanced. If a plain film demonstrates vertebral osteomyelitis, additional imaging is still warranted to assess the extent of disease and presence of complications (epidural or paraspinal abscess). Radionuclide scanning may be useful if MRI is contraindicated because of claustrophobia or presence of an implantable cardiac or cochlear device [1].

● Magnetic resonance imaging – MRI is the most sensitive radiographic technique for diagnosis vertebral osteomyelitis [31]. Typical MRI findings in vertebral osteomyelitis include (image 4) [32,33]:

• Decreased signal intensity in the vertebral bodies and disc and loss of endplate definition (T1- weighted images) (image 5).

• Increased disc signal intensity; less often, increased vertebral body signal intensity (T2-weighted images) (image 1).

• Contrast enhancement of the vertebral body and disc (image 6). Ring enhancement of paraspinal and epidural processes correlates with abscess formation, whereas homogeneous enhancement correlates with phlegmon formation.

Vertebral osteomyelitis rarely occurs without characteristic involvement of the intervertebral disc. For cases in which the disc is spared, an erroneous diagnosis of malignancy or compression fracture may be made [34].

MRI abnormalities consistent with osteomyelitis can be observed long before plain films become abnormal. In a review of 103 patients, MRI demonstrated changes suggestive of osteomyelitis in 91 percent of patients with symptoms of less than two weeks duration and in 96 percent of those with symptoms of more than two weeks duration [35].

False-negative MRI findings have been reported in patients with vertebral osteomyelitis and epidural abscess, especially in those with concurrent meningitis or with long, linear abscesses lacking discrete margins [36]. False-positive results can occur with bone infarction or fracture.

Radiographic findings in the setting of tuberculous vertebral osteomyelitis overlap with those seen in the setting of bacterial osteomyelitis. Extension into surrounding soft tissue tends to be more prominent in tuberculosis (TB) of the spine, and some patients with spinal TB have vertebral body abnormalities in the absence of disc space involvement. These issues are discussed further separately. (See "Skeletal tuberculosis", section on 'Radiography'.)

The role of follow-up MRI is discussed below. (See 'Role of imaging' below.)

● Computed tomography – CT demonstrates findings of vertebral osteomyelitis before changes are apparent on plain films (image 7). CT is also useful for detecting bony sequestra or involucra, adjacent soft tissue abscesses (image 8), and in localizing the optimal approach for a biopsy (image 9) [31].

Subtle abnormalities detected by CT, such as end plate irregularities, may not be specific for osteomyelitis, and early destructive changes may be missed. CT has a high false-negative rate for epidural abscess [31].

● Plain radiography – Plain radiographs are often normal in the early phases of infection. Typical findings in vertebral osteomyelitis consist of destructive changes of two contiguous vertebral bodies with collapse of the intervening disc space.

Bone destruction may not be apparent for three weeks or more after the onset of symptoms (image 10) [19,37]. Rarely, infection is confined to a single vertebra and produces collapse of the vertebral body, mimicking vertebral compression fracture [38,39].

Chest radiography is warranted in the setting of clinical suspicion for TB, but a normal chest film does not reduce clinical suspicion of spinal TB. (See "Diagnosis of pulmonary tuberculosis in adults" and "Skeletal tuberculosis".)

● Radionuclide scanning – Radioisotope studies may be useful adjuncts to diagnosis when radiographic changes on plain films or CT scans are absent or equivocal and the suspicion for osteomyelitis is high. They are relatively sensitive but their specificity for infection is low. Radionuclide scanning may be useful when MRI is contraindicated [40].

• Labeled-leukocyte scans are rarely useful for the diagnosis of vertebral osteomyelitis because abnormalities typically manifest as a nonspecific photopenic defect with a reduced uptake of isotope [41].

• Three-phase bone scintigraphy using labeled technetium is a relatively sensitive and specific test, but it may produce false-positive results in patients with noninfectious disorders such as fracture. False-negative results also can occur early in infection or in cases in which bone infarction accompanies bone infection.

• Gallium imaging is a sensitive and specific radionuclide scanning technique for vertebral

osteomyelitis. A typical positive test reveals intense uptake in two adjacent vertebrae with loss of the intervening disc space. In a series of 41 patients with suspected vertebral osteomyelitis, increased gallium uptake was detected in all of the 39 patients with biopsy-proven osteomyelitis; subsequent biopsy showed only degenerative changes in two patients with negative gallium scans [42].

• Positron emission tomography (PET) scanning using 18-fluorodeoxyglucose (FDG), especially when combined with CT (PET-CT), is highly sensitive, with a negative predictive value for vertebral osteomyelitis of close to 100 percent. The specificity is good but may be compromised by the presence of tumor, degenerative spinal disease, and/or spinal implants [43]. In one prospective study including 32 patients with suspected vertebral osteomyelitis who underwent both MRI and fluorine-18-fluorodeoxyglucose-PET/CT (18F-FDG-PET/CT), MRI was more useful for detection of epidural/spinal abscess and 18F-FDG-PET/CT was more useful for detection of metastatic infection [44].

Biopsy — In general, biopsy is warranted to confirm clinical and/or radiographic suspicion of vertebral osteomyelitis and to establish a microbiologic and histologic diagnosis.

Biopsy material is obtained via an open procedure or needle biopsy by CT guidance (image 9). In one study of 92 patients with vertebral osteomyelitis who had a biopsy, open biopsies had a higher microbiologic yield than needle biopsies (91 versus 53 percent) [45]. In a subsequent study including 129 patients with vertebral osteomyelitis, open biopsy had a higher diagnostic yield (70 percent) than fine needle aspirate (41 percent) or core biopsy (30 percent) [22]. In the setting of radiographic abnormality of the paravertebral soft tissue, diagnostic biopsy of this area may be reasonable even in the absence of a paravertebral abscess [46].

Clinicians should not be deterred from obtaining a biopsy if the patient has received antibiotics recently [45,47]. Prior antibiotic exposure is likely to reduce the yield, but not critically [48].

Samples should be sent for aerobic, anaerobic, mycobacterial, and fungal cultures and histopathology [19]. The sensitivity (measured by yield of positive cultures or Gram stain of aspirated material) varies between studies from a low of 50 percent [49] to a high of 73 to 100 percent [26,50].

Rarely, nucleic acid amplification testing may be useful if initial aerobic and anaerobic cultures are negative [1]. In one study including 19 patients with discitis, amplification-based DNA analysis of aspirated disc material correlated well with traditional culture methods [51]. A subsequent study demonstrated the potential value of 16S rRNA gene polymerase chain reaction (PCR) assay of biopsy material/aspirates as an adjunct to culture, although there were some false-positive results [52]. Contamination with skin flora is a potential problem with DNA-based diagnostic methods.

Additional tests — Additional diagnostic tests may be warranted based on epidemiologic factors; these include:

● Brucellosis serology – Brucellosis serologic testing is warranted in the setting of unexplained fever, https://www.uptodate.com/...rint?search=osteomyelitis&source=search_result&selectedTitle=8~150&usage_type=default&display_rank=8[19.03.2020 15:30:43] Vertebral osteomyelitis and discitis in adults - UpToDate

fatigue, and arthralgia in an individual with a possible source of exposure (eg, contact with animal tissues, ingestion of unpasteurized milk or cheese). Major endemic areas include countries of the Mediterranean basin, Persian Gulf, the Indian subcontinent, and parts of Mexico and Central and South America. (See "Brucellosis: Epidemiology, microbiology, clinical manifestations, and diagnosis".)

● Tuberculosis – Diagnostic evaluation for TB is warranted in the setting of relevant risk factors; these include a family history of TB, birth or long-term residence in a highly endemic region, HIV/AIDS, chest radiograph suggestive of latent TB infection, and/or diabetes. (See "Diagnosis of pulmonary tuberculosis in adults".)

Evaluation for endocarditis — Evaluation for concurrent IE is warranted in patients with underlying valvular disease and/or new-onset heart failure in the setting of positive blood cultures for gram-positive organisms [21,53,54]. This is warranted even though the duration of therapy for vertebral osteomyelitis (at least six weeks) is an adequate duration for treatment of IE in most cases. Patients with IE require additional follow-up evaluation for valvular disease as well as prophylactic antibiotics for prevention of subsequent IE. (See "Clinical manifestations and evaluation of adults with suspected left-sided native valve endocarditis", section on 'Echocardiography' and "Antimicrobial prophylaxis for the prevention of bacterial endocarditis".)

A retrospective review including 91 cases of vertebral osteomyelitis (excluding TB, brucellosis, and culture-negative and postsurgical cases) identified 28 patients (31 percent) with IE [53]. When patients with and without IE were compared, the following risk factors were significantly associated with coincident IE:

● Age >75 years [21] ● Predisposing heart condition ● Heart failure ● Positive blood cultures ● Infection due to gram-positive organisms, especially nonpyogenic streptococci or staphylococci

IE was less likely in patients with a urinary tract–presumed source of infection and with infection due to gram-negative organisms.

DIFFERENTIAL DIAGNOSIS

The differential diagnosis of vertebral osteomyelitis includes the following conditions; they are all distinguished radiographically.

● Spinal epidural abscess – Clinical manifestations of spinal epidural abscess include fever, back pain, and neurologic deficits. (See "Spinal epidural abscess".)

● https://www.uptodate.com/...rint?search=osteomyelitis&source=search_result&selectedTitle=8~150&usage_type=default&display_rank=8[19.03.2020 15:30:43] Vertebral osteomyelitis and discitis in adults - UpToDate

Psoas abscess – Clinical manifestations of psoas abscess include back or flank pain, fever, and pain with hip extension. (See "Psoas abscess".)

● Degenerative spine disease – Degenerative spine disease is common with aging, is associated with back pain, but does not usually result in radiculopathy. (See "Acute lumbosacral radiculopathy: Pathophysiology, clinical features, and diagnosis", section on 'Degenerative changes'.)

● Herniated disc – Clinical manifestations of disc herniation include back pain and radiculopathy. (See "Acute lumbosacral radiculopathy: Pathophysiology, clinical features, and diagnosis", section on 'Disc protrusion and level of injury'.)

● Metastatic tumor – Metastatic spinal tumor is typically associated with back pain in the setting of known malignancy; the most common primary cancers associated with skeletal metastasis include breast, prostate, thyroid, lung, and renal cancer. (See "Evaluation of low back pain in adults", section on 'Serious systemic etiologies' and "Epidemiology, clinical presentation, and diagnosis of bone metastasis in adults".)

● Vertebral compression fracture – Clinical manifestations of vertebral compression fracture consist of acute onset of localized back pain in the setting of risk factors for osteoporosis. (See "Evaluation of low back pain in adults", section on 'Less serious, specific etiologies'.)

TREATMENT

Management of vertebral osteomyelitis consists of antimicrobial therapy and percutaneous drainage of paravertebral abscess(es) if present. Timely surgical intervention is usually warranted for patients with neurologic deficits, radiographic evidence of epidural or paravertebral abscess, and/or cord compression (threatened or actual).

During the course of treatment for vertebral osteomyelitis, the pace of progression can change suddenly, with potential for catastrophic complications. Therefore, close observation (especially in the first two weeks after diagnosis) is essential. New neurologic manifestation(s), persistent back pain, and/or features of sepsis require immediate investigation.

Antimicrobial therapy

Clinical approach — Selection of antimicrobial therapy should be tailored to results of biopsy or blood culture.

If blood and biopsy cultures are negative and the clinical suspicion for vertebral osteomyelitis is high based on clinical and radiographic findings, initiation of empiric therapy is warranted. (See 'Empiric https://www.uptodate.com/...rint?search=osteomyelitis&source=search_result&selectedTitle=8~150&usage_type=default&display_rank=8[19.03.2020 15:30:43] Vertebral osteomyelitis and discitis in adults - UpToDate

therapy' below.)

Pathogen-directed therapy — No randomized controlled studies have compared antibiotic regimens for vertebral osteomyelitis. Choice of antibiotic therapy should be guided by biopsy or blood culture results:

● Staphylococcal spp – If the organism is found to be methicillin-susceptible Staphylococcus, we recommend treatment with an anti-staphylococcal penicillin such as nafcillin or oxacillin (2 g intravenously [IV] every 4 hours) or cefazolin (2 g IV every 8 hours); flucloxacillin is also an acceptable agent (not available in the United States).

If the Staphylococcus is methicillin resistant or if the patient is allergic to beta-lactam antibiotics, we favor beta-lactam desensitization or treatment with vancomycin (15 to 20 mg/kg/dose every 8 to 12 hours, not to exceed 2 g per dose). We do not use ceftriaxone as an alternative to cefazolin or antistaphylococcal penicillin in the absence of special circumstances (such as inability to give multiple daily intravenous doses). For patients who are unable to tolerate vancomycin due to allergy, daptomycin (6 mg/kg IV once daily) is an acceptable alternative.

● Streptococcal spp – If the streptococci is fully sensitive to penicillin (minimum inhibitory concentration [MIC] <0.12 mcg/mL), we recommend treatment with either ceftriaxone (2 g IV every 24 hours) or penicillin G (12 to 18 million units/day by continuous infusion or in six divided daily doses).

If the Streptococcus has intermediate susceptibility to penicillin (MIC between 0.12 and 0.5 mcg/mL), we typically treat with ceftriaxone (2 g IV every 24 hours). Alternatively, penicillin (24 million units/day per continuous infusion or in six divided daily doses) may be used. Patients with intermediate or fully resistant streptococci should be treated in collaboration with an infectious disease specialist. Specialized in vitro testing may be needed to select an appropriate antibiotic regimen for infections caused by fully resistant streptococci.

● Gram-negative bacilli – Choice of a specific agent for empiric therapy of gram-negative bacilli should be based on knowledge of the prevailing pathogens (and susceptibility patterns) within the health care setting. Initial treatment with one of the following is appropriate:

• Third-generation cephalosporin (ceftriaxone 2 g IV daily or ceftazidime 2 g IV every 8 hours or cefotaxime 2 g IV every 6 hours).

• Fourth-generation cephalosporin (cefepime 2 g IV every 8 to 12 hours). Dosing every 12 hours is sufficient in most cases; dosing every 8 hours is reasonable in patients with febrile neutropenia (particularly in the setting of known or suspected osteomyelitis due to Pseudomonas spp).

• Fluoroquinolone (ciprofloxacin 400 mg IV every 12 hours or 500 to 750 mg orally every 12 hours).

● Cutibacterium (formerly Propionibacterium) acnes – For treatment of infection due to C. acnes, we favor penicillin (20 to 24 million units IV daily by continuous infusion or in six divided doses) or ceftriaxone (2 g IV every 24 hours). Patients allergic to beta-lactams may be treated with vancomycin (15 to 20 mg/kg/dose every 8 to 12 hours, not to exceed 2 g per dose).

● Fungal infection – Treatment of fungal vertebral osteomyelitis is discussed separately. (See "Candida osteoarticular infections".)

Empiric therapy — Patients with negative Gram stain and culture results should be treated with an antimicrobial regimen with activity against the common causes of vertebral osteomyelitis, including staphylococci, streptococci, and gram-negative bacilli.

An appropriate empiric regimen consists of vancomycin (15 to 20 mg/kg/dose every 8 to 12 hours, not to exceed 2 g per dose) plus one of the following: cefotaxime (2 g IV every 6 hours), ceftazidime (1 to 2 g IV every 8 to 12 hours), ceftriaxone (2 g IV daily), cefepime (2 g IV every 12 hours), or ciprofloxacin (400 mg IV every 12 hours or 500 to 750 mg orally twice daily).

Anaerobes are uncommon pathogens in patients with vertebral osteomyelitis, and we do not routinely add anaerobic coverage to initial empiric therapy. Such coverage is warranted if clinical features suggest that the infection may be due to anaerobic organisms (such as in the setting of a concomitant intra- abdominal abscess) or if the Gram stain is positive but aerobic cultures are negative. In such cases, metronidazole (500 mg IV every six hours) may be added to the above regimen.

If empiric therapy does not result in objective clinical improvement (decreasing inflammatory markers, resolving fever and back discomfort) in three to four weeks, a repeat percutaneous needle biopsy or open surgical biopsy is required (algorithm 1).

Duration of therapy and follow-up — We routinely treat for a minimum of six weeks, with careful review to determine if further treatment is required [1,55]. Longer duration of therapy (eight weeks in some cases) is warranted for patients with undrained paravertebral abscess(es) and/or infection due to drug-resistant organisms (including methicillin-resistant S. aureus [MRSA]) [56]. In some cases, up to 12 weeks of therapy may be necessary, particularly in the setting of extensive bone destruction; the duration of therapy should be tailored to individual circumstances during the course of clinical follow-up. (See 'Clinical and laboratory monitoring' below.)

The above approach to duration of therapy is supported by the following studies:

● A randomized trial including 351 patients with vertebral osteomyelitis demonstrated that six weeks of antibiotic treatment was not inferior to 12 weeks of antibiotic therapy with respect to the proportion of patients cured at one year [55]. The number of patients with abscesses in the trial was low (19 percent), and computed tomography (CT)-guided drainage was needed in only 4 percent of cases. In addition, a short duration of intravenous therapy was administered (median 14 days); the most common oral antibiotic regimen was a fluoroquinolone with rifampin. The trial did not include patients with culture-negative infections. The most commonly isolated pathogen was S. aureus; https://www.uptodate.com/...rint?search=osteomyelitis&source=search_result&selectedTitle=8~150&usage_type=default&display_rank=8[19.03.2020 15:30:43] Vertebral osteomyelitis and discitis in adults - UpToDate

fluoroquinolones are not regarded as ideal drugs for treatment of staphylococcal infections.

● A retrospective review including 314 patients with vertebral osteomyelitis noted that independent risk factors conferring an increased likelihood of relapse in patients treated <8 weeks included presence of undrained paravertebral abscess(es) and MRSA infection; in the absence of these findings, the likelihood of relapse in patients treated <8 weeks was much lower [56].

Following at least two weeks of parenteral therapy, completion of treatment with oral therapy may be reasonable in the following circumstances [1,57,58]:

● The infection is uncomplicated and the patient has no significant comorbidities. ● A favorable clinical response to initial parenteral therapy is observed. ● A suitable drug is available, with proven susceptibility to the causative organism and excellent bioavailability. ● There is a high chance of reliable absorption of oral medication. Clinicians should check for concomitant medication that may hinder absorption. ● Compliance with oral therapy can be assured or carefully monitored.

Oral antibiotic regimens for completing treatment of vertebral osteomyelitis are summarized in the table (table 2).

Patients with laboratory and radiographic evidence of treatment failure warrant repeat tissue biopsy (via image-guided aspiration or surgery) for microbiologic and histologic examination.

Clinical and laboratory monitoring — During antimicrobial therapy, patients should be followed carefully for clinical signs of soft tissue extension, paraspinal abscess, and cord compression.

Patients should also be followed with weekly monitoring of inflammatory markers (erythrocyte sedimentation rate [ESR] and C-reactive protein [CRP]) [1]. In one retrospective study including 44 patients with vertebral osteomyelitis, those without a significant decline in the ESR during the first month of therapy were more likely to fail medical therapy (9 of 18 cases compared with 3 of 26 cases with a >50 percent fall in ESR) [28]. However, a rapid decline was not common: the ESR either rose or failed to decline during the first two weeks of treatment in 19 of 32 patients who were ultimately cured with medical therapy. Similar findings have been reported by others [59]. CRP normalizes more rapidly than the ESR after successful treatment of spinal infections and after uncomplicated spinal fusion surgery [31].

Role of imaging — Routine follow-up imaging studies are not necessary. Regular imaging during treatment and in the presence of clinical improvement will not benefit the outcome. Magnetic resonance imaging (MRI), CT, and plain films may appear to worsen for several weeks after the initiation of antibiotic therapy that will be ultimately successful [35].

Follow-up imaging studies are warranted in patients whose clinical status has not improved at the planned time for discontinuation of antibiotics in order to evaluate for the presence of an abscess in need of drainage or to detect spinal instability amenable to surgical intervention [1]. https://www.uptodate.com/...rint?search=osteomyelitis&source=search_result&selectedTitle=8~150&usage_type=default&display_rank=8[19.03.2020 15:30:43] Vertebral osteomyelitis and discitis in adults - UpToDate

The utility of obtaining imaging studies four to eight weeks after completion of treatment of vertebral osteomyelitis was examined in a retrospective study including 79 patients [60]; none of 27 patients who demonstrated improvement in follow-up MRI studies had evidence of treatment failure after one year of follow-up. In contrast, 5 of 38 patients (13 percent) and 4 of 14 patients (29 percent) whose initial follow- up images demonstrated equivocal changes or evidence of radiographic worsening subsequently failed medical treatment during long-term follow-up.

Associated hardware — Development of vertebral osteomyelitis in the presence of spinal hardware typically reflects a complication of the hardware placement. Most patients have an associated wound infection, although rarely hematogenous seeding of hardware can occur. In such cases, treatment should be based on culture data obtained from wound drainage and/or operative debridement. Typically such infections are treated with intravenous antimicrobial therapy tailored to culture results until bone fusion has been achieved (at least six weeks). If removal of the hardware following union is feasible, repeat cultures should be obtained at the time of hardware removal to guide subsequent therapy, which typically includes at least another six weeks of antimicrobial therapy. If hardware removal is not feasible, antimicrobial suppression (tailored to culture and susceptibility data) may be required either after or in lieu of a long course of parenteral therapy. Rarely oral therapy can be used as primary therapy if the causative organism is susceptible to an oral agent such as fluoroquinolone.

Issues related to treatment of infections associated with hardware are discussed further separately. (See "Osteomyelitis in adults: Treatment", section on 'Presence of orthopedic hardware'.)

Surgery — Indications for surgery include [1,19]:

● Presence of neurologic deficits ● Presence of epidural or paravertebral abscesses in need of drainage (see "Spinal epidural abscess") ● Threatened or actual cord compression due to vertebral collapse and/or spinal instability ● Progression, persistence, or recurrence of disease (as documented by persistently positive blood cultures or worsening pain) despite appropriate antimicrobial therapy

There are no randomized trials evaluating surgical management of vertebral osteomyelitis [1]. Placing hardware in the setting of spinal infection has raised concern regarding recurrent or chronic infection due to adherence of bacteria to foreign material. It is common practice to administer an additional six-week 'tail' of oral antibiotics, although there is little evidence to guide management. One retrospective study has indicated that, when spinal stabilization is required, timely instrumentation may be safe in the setting of appropriate selection and duration of antimicrobial therapy [61]. Another study reported outcomes for 100 patients with vertebral osteomyelitis who underwent a variety of surgical procedures, which were highly variable; approximately one-quarter of patients had residual pain and a similar proportion required repeat surgery [62].

In contrast to the preceding study, a report of 42 patients with vertebral osteomyelitis who required surgery, 40 had complete resolution of their deficits with no recurrences following a two-stage procedure

that included anterior debridement and strut grafting followed by delayed instrumented posterior fusions [63]. Patients received an average of 14.4 days of intravenous antibiotics after the anterior debridement and six weeks of intravenous therapy following the posterior instrumentation. (See 'Prognosis' below.)

In general, paravertebral abscess can be managed by CT-guided catheter drainage. Epidural abscess in the setting of neurologic deficit should be managed with surgical intervention; this may include open drainage, bone debridement, and interbody fusion (with or without bone grafting and posterior instrumentation). (See "Spinal epidural abscess".)

Adjunctive measures — Bed rest and analgesics are generally helpful in managing pain after the diagnosis is established. A fitted back brace often provides substantial back relief and enhances mobility for patients with severe pain. Clinicians should have a low threshold for referral to a specialist pain service.

Early bed rest may be particularly important, especially in lumbar osteomyelitis. When the patient is upright, the whole weight of the upper body is transmitted to the point of active infection. It is our practice to put patients with severe pain to bed for at least 10 days and use intensive in-bed, non-weight bearing physical therapy and long-acting oral analgesics. In such circumstances, prophylactic measures for prevention of deep venous thrombosis are warranted. (See "Prevention of venous thromboembolic disease in acutely ill hospitalized medical adults".)

PROGNOSIS

The most serious complication of vertebral osteomyelitis is neurologic impairment secondary to either abscess formation or bony collapse. Most patients have gradual improvement in back pain after therapy is begun, and the pain typically disappears after bone fusion occurs. However, back pain can persist. The best way to reduce the morbidity and mortality associated with vertebral osteomyelitis is to minimize the time between the onset of symptoms and the initiation of appropriate therapy.

The long-term outcome in vertebral osteomyelitis was evaluated in a retrospective study of 253 patients with vertebral osteomyelitis with median duration of follow-up 6.5 years (range 2 days to 38 years) [64]. Relapse occurred in 14 percent and residual symptoms occurred in 31 percent; 11 percent died (all- cause mortality). Surgery was performed in 43 percent of patients and was successful in 79 percent of cases. Independent risk factors for death or residual symptoms included neurologic compromise at the time of diagnosis (eg, motor weakness, spinal instability, paralysis), nosocomial acquisition of infection, and delay in diagnosis. The results of this study need to be interpreted with caution since cases were collected over a long time period (1950 to 1994), which means that some cases occurred prior to the development of modern imaging and diagnostic techniques.

In another study including 260 patients with vertebral osteomyelitis, three-quarters of treatment failures occurred within 4.7 months of diagnosis [4]. Multivariate analysis indicated that infection with S. aureus was associated with increased risk of relapse. Longer-term outcomes included neurological deficit (16

percent) and persistent back pain (32 percent).

Major depression is a well-recognized complication of chronic back pain (about a third of patients) and is an important potential long-term consequence [65,66].

Overall morbidity and mortality tends to increase with age [67]; this may be related to delayed diagnosis (especially when people have background degenerative spinal disease or have communication difficulties), multiple comorbidities, and age-related frailty [68]. Older patients are also more likely to have concomitant infective endocarditis (IE); in one study including 351 patients with vertebral osteomyelitis (85 of whom were ≥75 years of age), IE was diagnosed in 37 percent of patients ≥75 years compared with 14 percent of patients <75 years [69].

Mortality — Prior to the discovery of antibiotics, vertebral osteomyelitis was fatal in approximately 25 percent of cases [13]. Mortality due to vertebral osteomyelitis in the antibiotic era is less than 5 percent, and the rate of residual neurologic deficits among survivors is less than 7 percent. Delays in diagnosis can lead to disabling complications [1].

In a large retrospective study including more than 7000 patients with vertebral osteomyelitis, in-hospital mortality (6 percent) was largely determined by comorbidities including diabetes, end-stage kidney disease, cirrhosis, and malignancy [70].

SOCIETY GUIDELINE LINKS

SUMMARY

● Vertebral osteomyelitis occurs by three basic routes: hematogenous spread from a distant site or focus of infection (this is the most common mechanism), direct inoculation from trauma or spinal surgery, and contiguous spread from adjacent soft tissue infection. (See 'Mechanisms of infection' above.)

● The most important infecting organism in vertebral osteomyelitis is Staphylococcus aureus, accounting for more than 50 percent of cases. Other pathogens include nonpyogenic streptococci, pyogenic streptococci including groups B and C/G, enteric gram-negative bacilli, Candida spp, Pseudomonas aeruginosa, Brucella spp, and Mycobacterium tuberculosis. (See 'Microbiology' above.)

● The major clinical manifestation of vertebral osteomyelitis is back or neck pain, with or without fever. The most common clinical finding is local tenderness to percussion over the involved posterior

spinous processes. The most common laboratory abnormalities are elevated erythrocyte sedimentation rate and C-reactive protein. (See 'Clinical features' above.)

● Vertebral osteomyelitis should be suspected on the basis of clinical features and radiographic studies (magnetic resonance imaging is the most sensitive radiographic technique) and confirmed by biopsy of the infected intervertebral disc space or vertebral bone. Blood cultures are positive in up to 50 to 70 percent of patients; a biopsy may not be necessary in patients with clinical and radiographic findings typical of vertebral osteomyelitis and positive blood cultures with a likely pathogen. (See 'Diagnosis' above.)

● Every effort should be made to identify the pathogen(s) before starting antimicrobial treatment. In patients with suspected vertebral osteomyelitis, we favor the clinical approach described above and summarized in the algorithm (algorithm 1). Evaluation for concurrent infectious endocarditis may be warranted in select patients. (See 'Suggested clinical approach' above.)

● Most cases of vertebral osteomyelitis respond to antimicrobial therapy. Surgery is necessary in a minority of patients with vertebral osteomyelitis; prompt surgery is warranted for patients with focal neurologic deficits, epidural or paravertebral abscess, and/or cord compression. (See 'Treatment' above and 'Surgery' above.)

● If possible, antimicrobial therapy should be withheld until a microbiologic diagnosis is confirmed. Clinical exceptions include neurologic compromise and sepsis; in these circumstances, empiric antibiotic therapy is warranted. Choice of antibiotic therapy should be guided by biopsy or blood culture results if available. For patients with negative culture results, empiric treatment is warranted based on the most likely organisms to cause infection. (See 'Clinical approach' above.)

● We routinely treat for a minimum duration of six weeks. Longer duration of therapy (at least eight weeks) is warranted for patients with undrained paravertebral abscess(es) and/or infection due to drug-resistant organisms (including methicillin-resistant S. aureus). The duration of therapy should be tailored to individual circumstances during the course of clinical follow-up. (See 'Duration of therapy and follow-up' above.)

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61. Park KH, Cho OH, Lee YM, et al. Therapeutic outcomes of hematogenous vertebral osteomyelitis with instrumented surgery. Clin Infect Dis 2015; 60:1330.

62. Valancius K, Hansen ES, Høy K, et al. Failure modes in conservative and surgical management of infectious spondylodiscitis. Eur Spine J 2013; 22:1837.

63. Dimar JR, Carreon LY, Glassman SD, et al. Treatment of pyogenic vertebral osteomyelitis with anterior debridement and fusion followed by delayed posterior spinal fusion. Spine (Phila Pa 1976) 2004; 29:326.

64. McHenry MC, Easley KA, Locker GA. Vertebral osteomyelitis: long-term outcome for 253 patients from 7 Cleveland-area hospitals. Clin Infect Dis 2002; 34:1342.

65. Von Korff M, Crane P, Lane M, et al. Chronic spinal pain and physical-mental comorbidity in the United States: results from the national comorbidity survey replication. Pain 2005; 113:331.

66. Demyttenaere K, Bruffaerts R, Lee S, et al. Mental disorders among persons with chronic back or neck pain: results from the World Mental Health Surveys. Pain 2007; 129:332.

67. Zarrouk V, Gras J, Dubée V, et al. Increased mortality in patients aged 75 years or over with pyogenic vertebral osteomyelitis. Infect Dis (Lond) 2018; 50:783.

68. Amadoru S, Lim K, Tacey M, Aboltins C. Spinal infections in older people: an analysis of demographics, presenting features, microbiology and outcomes. Intern Med J 2017; 47:182.

69. Courjon J, Lemaignen A, Ghout I, et al. Pyogenic vertebral osteomyelitis of the elderly: Characteristics and outcomes. PLoS One 2017; 12:e0188470.

70. Akiyama T, Chikuda H, Yasunaga H, et al. Incidence and risk factors for mortality of vertebral osteomyelitis: a retrospective analysis using the Japanese diagnosis procedure combination database. BMJ Open 2013; 3.

Topic 7663 Version 41.0

GRAPHICS

Discitis lumbar spine and epidural abscess on T2-weighted MRI

A T2-weighted image of the lumbar spine (A) shows an epidural abscess (arrow) extending from the abnormal disc space between L1 and L2 (arrowhead). There is increased signal in the disc. Image B is a magnified view and shows the epidural abscess (arrow) and an abnormal, high intensity disc (arrowhead). The patient received an epidural injection two weeks prior to presentation.

MRI: magnetic resonance imaging.

Graphic 91707 Version 4.0

Osteomyelitis lumbar spine s/p AAA repair

A lateral examination of the lumbar spine (A) shows erosive scalloping of the L2 and L3 vertebral bodies (arrows). Image B is a magnified view of an abscess (arrow) surrounding the aortic graft (arrowhead) and eroding into the vertebral body (dashed arrow). Image C is a bone window of L3 that shows destruction of the vertebral body by the perigraft abscess.

s/p: status post; AAA: abdominal aortic aneurysm.

Graphic 91706 Version 2.0

Vertebral osteomyelitis causing a psoas abscess on CT

Image A is a CT scan through the lower abdomen and shows bony destruction of a lumbar vertebral body (arrow) with a swollen right psoas muscle (arrowhead). Image B is a CT scan through the upper pelvis and shows an abscess in the right psoas muscle (arrow).

CT: computed tomography.

Graphic 91708 Version 1.0

Complications of vertebral osteomyelitis

Short-term complications Longer-term complications

Epidural abscess, subdural abscess, meningitis Residual neurological deficit(s) Paraspinal abscess and extension (including psoas, Chronic back pain retropharyngeal, mediastinal, subphrenic, retroperitoneal Depression abscesses, or empyema) Extension of infection involving the aorta and/or vena cava Spinal cord and/or nerve root impingement with neurological consequences Vertebral body collapse Endocarditis*

* In general, vertebral osteomyelitis is a complication of bacteremia; associated endocarditis may or may not be present.

Graphic 100372 Version 2.0

Clinical approach to vertebral osteomyelitis in adults

ESR: erythrocyte sedimentation rate; CRP: C-reactive protein; MRI: magnetic resonance imaging; CT: computed tomography. * Additional diagnostic testing may be warranted based on epidemiologic factors (eg, to evaluate for infection due to brucellosis or tub discitis in adults for discussion. ¶ Refer to the UpToDate topic on vertebral osteomyelitis and discitis in adults for discussion of characteristic radiographic findings, dif Δ A needle biopsy may not be necessary in patients with clinical and radiographic findings typical of vertebral osteomyelitis and positiv vertebral osteomyelitis and discitis in adults for further discussion. ◊ Biopsy material should be sent for bacterial (aerobic and anaerobic) culture, fungal culture, and mycobacterial culture in addition to

Graphic 104402 Version 2.0

Three magnetic resonance images of vertebral osteomyelitis due to methicillin- resistant Staphylococcus aureus

(A) T2-weighted axial image shows collections in the psoas muscles bilaterally (arrows) representing abscesses. (B) T2-weighted sagittal image demonstrates increased signal in the L2/3 and L3/4 intervertebral disc spaces (arrows). (C) Post-contrast sagittal fat saturated T1-weighted image shows enhancement in the intervertebral disc spaces (arrows) and adjacent L2 to L4 vertebral bodies (arrowheads).

Courtesy of Jenny Hoang, MBBS, Duke University Medical Center.

Graphic 87174 Version 4.0

Osteomyelitis lumbar spine on T1-weighted MRI

A T1-weighted image of the lumbar spine (A) shows decreased signal intensity of the vertebral bodies (arrows) and loss of endplate definition (arrowhead). Image B is a magnified view of the ill- defined low intensity disc (arrowhead). There is poor definition of the disc with the low intensity end plates (arrows).

MRI: magnetic resonance imaging.

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Osteomyelitis lumbar spine on T1 contrast-enhanced MRI

A contrast-enhanced MRI of the lumbar spine (A) shows enhancement of the end plates and the vertebral bodies (arrows). Image B is a magnified view of the lumbar spine showing enhancement of the opposing endplates and vertebral bodies (arrows).

MRI: magnetic resonance imaging.

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Vertebral osteomyelitis on CT

Image A is a sagittal reconstruction of the lumbar spine showing disc space widening (arrow) and subtle destruction of the opposing endplates not appreciated on plain radiograph. Image B shows more advanced destruction of bone on either side of the joint space (arrows).

CT: computed tomography.

Graphic 91710 Version 3.0

Vertebral osteomyelitis and paravertebral abscess on CT

Image A is an axial CT through the thorax showing vertebral bony destruction with a paravertebral abscess (arrow head). In image B, the paravertebral abscess is overlaid in orange.

CT: computed tomography.

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Aspiration of a paravertebral abscess under CT guidance

Image A is a CT scan with the patient in left decubitus position and shows a right-sided paravertebral abscess. Image B shows the tip of the needle as it advances toward the abscess.

CT: computed tomography.

Graphic 91712 Version 2.0

Cervical osteomyelitis on radiograph and MRI

Image A is a lateral radiograph of the spine showing bony destruction of C4 (arrow) and C5 (arrowhead) with kyphosis. Image B is a T1-weighted MRI sequence with fat saturation following gadolinium and shows enhancement of C4 and C5 (arrows) and their posterior elements (arrowhead).

MRI: magnetic resonance imaging.

Graphic 91709 Version 3.0

◊

§ https://www.uptodate.com/...rint?search=osteomyelitis&source=search_result&selectedTitle=8~150&usage_type=default&display_rank=8[19.03.2020 15:30:43] Vertebral osteomyelitis and discitis in adults - UpToDate

Oral antibiotic regimens for completing treatment of vertebral osteomyelitis in adults*

Infectious agent Antibiotic regimen¶ Dosing

Staphylococci, methicillin One of the following: susceptible RifampinΔ plus one of the 300 to 450 mg twice daily following:

Levofloxacin 500 to 750 mg once daily

Ciprofloxacin 500 to 750 mg twice daily

Fusidic acid (where 500 mg three times daily available)◊

Clindamycin 300 to 450 mg three times daily

Staphylococci, methicillin resistant One of the following:

RifampinΔ plus one of the 300 to 450 mg twice daily following:

Levofloxacin 500 to 750 mg once daily

Ciprofloxacin 500 to 750 mg twice daily

Fusidic acid (where 500 mg three times daily available)◊

Clindamycin 300 to 450 mg three times daily

Linezolid 600 mg twice daily

Gram-negative organisms One of the following:

Ciprofloxacin§ 500 to 750 mg twice daily

Levofloxacin§ 500 to 750 mg once daily

Trimethoprim-sulfamethoxazole 1 double-strength tablet twice daily

Penicillin-sensitive streptococci One of the following:

Amoxicillin¥ 750 to 1000 mg three times daily

Clindamycin 300 to 450 mg three times daily

* Following at least two weeks of parenteral therapy, completion of treatment with oral therapy may be reasonable in some circumstances; refer to UpToDate for further discussion. ¶ The choice of antibiotic regimen should be based on susceptibility, as well as patient drug allergies, intolerances, and potential drug-drug interactions or contraindications to a specific agent. Δ Rifampin should not be used alone; it must be combined with a second agent to reduce the likelihood of selection for drug resistance. ◊ Fusidic acid is not available in the United States. Fusidic acid should not be used alone; it must be combined with a second agent to reduce the likelihood of selection for drug resistance. When rifampicin is combined with fusidic acid, fusidic acid levels may be reduced.[1] § Ciprofloxacin and levofloxacin have activity against Pseudomonas aeruginosa. For P. aeruginosa the higher dose range of fluoroquinolone should be used; ciprofloxacin 750 mg every 12 hours or levofloxacin 750 mg once daily. ¥ Oral amoxicillin therapy may be considered after an initial period of intravenous therapy for the management of penicillin- susceptible streptococci.

Reference: 1. Pushkin R, Iglesias-Ussel MD, Keedy K, et al. A randomized study evaluating oral fusidic acid (CEM-102) in combination with oral rifampin compared with standard-of-care antibiotics for treatment of prosthetic joint infections: a newly identified drug-drug interaction. Clin Infect Dis 2016; 63:1599. Data from:

1. Société de Pathologie Infectieuse de Langue Français (SPILF). Primary infectious spondylitis and following intradiscal procedure, without prosthesis. Recommendations. Med Mal Infect 2007; 37:573. 2. Berbari EF, Kanj SS, Kowalski TJ, et al. 2015 Infectious Diseases Society of America (IDSA) clinical practice guidelines for the diagnosis and treatment of native vertebral osteomyelitis in adults. Clin Infect Dis 2015; 61:e26. 3. Bernard L, Dinh A, Ghour I, et al Antibiotic treatment for 6 weeks versus 12 weeks in patients with pyogenic vertebral osteomyelitis: an open-label, non-inferiority, randomised, controlled trial. Lancet 2015; 385:875. 4. Li H-K, Rombach I, Zambellas R, Oral versus Intravenous Antibiotics for Bone and Joint Infection. NEJM 2019; 380:425.

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Contributor Disclosures

Malcolm McDonald, PhD, FRACP, FRCPA Nothing to disclose Trisha Peel, MD, MBBS Consultant/Advisory Boards: Merck Sharp & Dohme [Infections in intensive care units (Ceftolozane/tazobactam)]. Denis Spelman, MBBS, FRACP, FRCPA, MPH Nothing to disclose Elinor L Baron, MD, DTMH Nothing to disclose

Conflict of interest policy

Contributor Disclosures

Conflict of interest policy

https://www.uptodate.com/...rint?search=osteomyelitis&source=search_result&selectedTitle=8~150&usage_type=default&display_rank=8[19.03.2020 15:30:43] Prosthetic joint infection: Epidemiology, microbiology, clinical manifestations, and diagnosis - UpToDate

View Outline  Bookmark Tools Authors: Elie Berbari, MD, FIDSA, Larry M Baddour, MD, FIDSA, FAHA, Antonia F Chen, MD, MBA Section Editor: Denis BackSpelman, to Search MBBS, FRACP, FRCPA, MPH Deputy Editor: Elinor L Baron, MD, DTMH

ProstheticContributor Disclosures joint infection: Epidemiology, microbiology, clinical manifestations, and diagnosis

All topics are updated as new evidence becomes available and our peer review process is complete.

Literature review current through: Feb 2020. | This topic last updated: Sep 16, 2019.

INTRODUCTION

Prosthetic joint infection (PJI) is a serious complication of prosthetic joint implantation [1-8]. The epidemiology, microbiology, clinical manifestations, and diagnosis of PJI will be reviewed here. Infections associated with other implanted orthopedic devices, such as pins and rods, will not be specifically discussed, but similar principles may apply.

Issues related to treatment and prevention of PJIs are discussed separately. (See "Prosthetic joint infection: Treatment" and "Prevention of prosthetic joint and other types of orthopedic hardware infection".)

EPIDEMIOLOGY

Nearly one million total hip arthroplasties (THAs) or total knee arthroplasties (TKAs) are performed in the United States each year. It is estimated that, by 2030, nearly two million THAs or TKAs will be performed in the United States annually [9].

The risk of PJI is greater for knee arthroplasty than hip arthroplasty [1,10]. The rate of PJI in most centers ranges between 0.5 to 2 percent for knee replacements, 0.5 to 1.0 percent for hip replacements, and <1 percent for shoulder replacements [11,12]. The higher rate of PJI in knee arthroplasties may be attributable to greater mobility in the joint and soft tissue and less protective soft tissue coverage.

PJI rates appear to be declining. In a retrospective study including more than 10,700 patients in Taiwan who underwent primary TKA between 2002 and 2014, the rate of PJI declined from 1.9 percent (2002 to 2006) to 0.76 percent (2011 to 2014) [13]. Similarly, in a review including more than 11,800 patients in the United States who underwent primary THA or TKA, the incidence of PJI between 2008 and 2016 fell from 1.4 to 0.6 percent [14]. In another cohort including more than 679,000 patients in the United Kingdom who underwent primary TKA between 2003 and 2013, the infection rate was 0.5 percent [15].

In general, the rate of PJI is highest during the first two years following surgery [1]. In one study involving more than 69,000 patients undergoing elective TKA followed longitudinally from 1997 to 2006,

https://www.uptodate.com/...stations-and-diagnosis?search=osteomyelitis&topicRef=7668&source=see_link#PATIENT_INFORMATION[19.03.2020 15:31:39] Prosthetic joint infection: Epidemiology, microbiology, clinical manifestations, and diagnosis - UpToDate

the rate of PJI during the first two years following surgery was 1.5 percent; the rate of PJI 2 to 10 years after joint replacement was 0.5 percent [16].

Risk factors — Risk factors for PJI include [1,17-24]:

● Presence of comorbidities such as rheumatoid arthritis, diabetes mellitus, malignancy, chronic kidney disease, obesity, lymphedema, immunosuppression ● Use of prednisone, tumor necrosis factor inhibitors, and other biologic disease-modifying antirheumatic drugs ● Prior arthroplasty or prior infection at the surgical site ● American Society of Anesthesiologists score ≥3 (table 1) ● Prolonged duration of surgery ● Postoperative complications such hematoma, wound dehiscence ● Staphylococcus aureus bacteremia [25]

DEFINITIONS

PJIs are often categorized as early onset (<3 months after surgery), delayed onset (3 to 12 months after surgery), and late onset (>12 months after surgery). However, these definitions are controversial and not always clear-cut, particularly in patients for whom the diagnosis is delayed [26]. There is considerable overlap between early- and delayed-onset PJIs, and hip PJIs tend to occur sooner than knee PJIs.

The timing of infection onset has implications for surgical management (eg, implant retention versus removal). These issues are discussed further separately. (See "Prosthetic joint infection: Treatment".)

MICROBIOLOGY

Pathogens — The timing of infection can be a clue as to the identity of the infecting organism. Early- onset infections are often due to S. aureus, gram-negative bacilli, anaerobes, or polymicrobial infection [1]. Delayed-onset infections are often due to coagulase-negative staphylococci, Cutibacterium (Propionibacterium) species, or enterococci. Late-onset infections are often due to S. aureus, gram- negative bacilli, or beta-hemolytic streptococci. (See 'Clinical manifestations' below.)

In the setting of PJI due to coagulase-negative staphylococci, species identification may be useful in some circumstances. For example, Staphylococcus lugdunensis is a coagulase-negative Staphylococcus that shares some aspects of virulence with S. aureus but is often susceptible to beta- lactam antibiotics, including oxacillin [27]. (See "Staphylococcus lugdunensis".)

Cutibacterium acnes is a relatively common cause of PJI following shoulder arthroplasty (16 percent in one study) but is a rare cause of infection following hip or knee arthroplasty [28-30]. Cutibacterium

avidum has been observed as a cause of hip PJI, and colonization of the groin in obese patients may be a risk factor for hip PJI [31,32]. (See "Invasive Cutibacterium (formerly Propionibacterium) infections", section on 'Orthopedic infection'.)

Rare causes of PJI include fungal infection (most often Candida spp) and mycobacterial infection (Mycobacterium tuberculosis and rapidly growing mycobacteria). (See "Skeletal tuberculosis", section on 'Prosthetic joint infection' and "Rapidly growing mycobacterial infections: Mycobacteria abscessus, chelonae, and fortuitum", section on 'Prosthetic device infection'.)

Cultures are negative in 7 to 39 percent of patients with suspected PJI [33]. In general, cultures are commonly positive in the setting of early-onset PJI, but frequently negative in patients who present indolently with a loose, painful prosthesis. Cultures may be negative if insufficient tissue is sent for culture or if only swabs are obtained. In addition, antibiotic administration prior to culture collection diminishes culture yield [1,34]. In some cases, "culture-negative" PJI may be attributable to small colony variants of staphylococci, due to slow growth of these variants [35]. Fastidious pathogens associated with culture-negative PJI include Coxiella burnetii, brucellosis, bartonellosis, mycoplasma, mycobacteria, and fungi [36].

Biofilm — Presence of orthopedic hardware enhances susceptibility to infection due to formation of a biofilm [37,38]. The process of biofilm formation consists of bacterial adherence to hardware, followed by multiplication and elaboration of exopolysaccharides ("glycocalyx"); over time, microcolonies of bacteria encased in glycocalyx coalesce to form biofilm [39,40].

Bacteria near the surface of the biofilm are usually metabolically active and have access to nutrients that diffuse through the upper surface. Bacteria deep within the biofilm are metabolically inactive or in various stages of dormancy and are protected from host defenses [39].

The microenvironment within a biofilm may adversely affect antimicrobial mechanisms, and diffusion of antimicrobial agents through biofilm may be limited or slow [40]. Soon after a biofilm is established, the susceptibility of bacteria to antimicrobial agents often demonstrates a logarithmic decline [41]. In the presence of biofilm, antibiotic administration may be associated with an initial clinical response, followed by relapse within days or months of stopping antibiotic therapy, unless the hardware is removed.

Presence of organisms in biofilm may explain the propensity of PJI to manifest weeks or months after surgery. It may also explain the difficulty associated with pathogen identification in patients with indolent, late-onset PJIs.

Given the slow metabolic rate of organisms in biofilm, suppressive antibiotic therapy may be successful in some cases; however, such therapy may ultimately fail in the absence of hardware removal.

CLINICAL MANIFESTATIONS

Signs and symptoms — The clinical manifestations of PJI depend on the timing of symptom onset: early onset (<3 months after surgery), delayed onset (3 to 12 months after surgery), or late onset (>12 months after surgery).

Early-onset infection is usually acquired during implantation. Less commonly, it can arise in the setting of postoperative wound dehiscence with contiguous spread of organisms from the superficial wound to the deeper structures. These infections are frequently associated with hematoma formation or superficial necrosis of the incision. Most early-onset infections present with the acute onset of one or more of the following findings: joint pain, warmth, erythema, induration or edema at the incision site, wound drainage or dehiscence, joint effusion, and fever.

Delayed-onset infection is often acquired during implantation; it typically presents with an indolent course characterized by persistent joint pain, with or without early implant loosening. Fever is present in less than half of cases [1]. Sinus tract associated with intermittent drainage may be observed; this finding on its own may be considered diagnostic of PJI [3]. In the absence of a sinus tract, physical exam findings are often minimal; if swelling is present, it is usually slight. Delayed-onset infections may be difficult to distinguish from aseptic failure of the prosthetic joint. PJI is often associated with persistent joint pain, while mechanical loosening commonly causes pain with joint motion and weight bearing (which abates with rest) [42,43]. (See 'Differential diagnosis' below.)

Late-onset PJI often occurs in the setting of hematogenous seeding from infection at another site (such as vascular catheter, urinary tract, or soft tissue infection) [44]. Patients with late-onset PJI typically present with acute onset of systemic symptoms associated with bacteremia (similar to early-onset infection), including joint pain in a previously well-functioning joint, warmth, erythema, induration or edema at the incision site, joint effusion, and fever. Dislocation may occur [45]. It is not always possible to determine whether a PJI arose hematogenously; in one study including 50 cases of hematogenous PJI, the median time of onset was nearly five years after surgery and a distant source for the infection was identified in only approximately half of the cases [46].

The timing of infection may be an important clue as to the identity of the infecting organism. (See 'Microbiology' above.)

Asymptomatic infection — Asymptomatic PJI may be detected incidentally in the setting of revision surgery for other indications [47]. In one study including more than 600 hip or knee arthroplasty revision surgeries, PJI (defined as two or more positive cultures with the same organism) was diagnosed in 10 percent of cases [48].

DIAGNOSIS

Clinical approach — PJI should be suspected patients with a joint prosthesis and relevant signs and symptoms of infection (including joint pain, warmth, erythema, induration, or edema at the incision site, sinus tract or persistent wound drainage, wound dehiscence, joint effusion, or fever) [5]. https://www.uptodate.com/...stations-and-diagnosis?search=osteomyelitis&topicRef=7668&source=see_link#PATIENT_INFORMATION[19.03.2020 15:31:39] Prosthetic joint infection: Epidemiology, microbiology, clinical manifestations, and diagnosis - UpToDate

The diagnosis of PJI can be challenging because the definition is not standardized; a number of diagnostic criteria have been proposed, including the 2018 International Consensus Meeting (ICM) criteria, the 2013 ICM criteria, the 2013 Infectious Disease Society of America guidelines, and the 2011 Musculoskeletal Infection Society (MSIS) criteria (table 2) [4-8]. We favor the MSIS 2011 diagnostic criteria, which are used most widely. (See 'Synovial fluid analysis' below.)

In general, the diagnosis rests on a combination of factors including history and physical examination, synovial fluid analysis, serum inflammatory markers, culture data, and intraoperative findings [2]. Discriminating between chronic PJI and aseptic joint failure can be challenging. (See 'Differential diagnosis' below.)

The diagnosis of PJI may be established in any of the following circumstances [4,5] (see 'Interpreting test results' below):

● Presence of a sinus tract that communicates with the prosthesis

● Two or more periprosthetic cultures with phenotypically identical organisms (≥2 intraoperative cultures or a combination of preoperative synovial fluid aspiration culture and intraoperative tissue culture)

• A single positive culture with a virulent organism (such as S. aureus) may also represent PJI.

• A single culture due to an organism of relatively low virulence (such as Staphylococcus epidermidis, Corynebacterium species, Cutibacterium species, or Bacillus species) is generally considered a contaminant. Such organisms may be presumed to represent a true pathogen if the same organism is observed in multiple cultures; these cases should be evaluated in the context of other available evidence (such as intraoperative Gram stain or tissue biopsy).

Findings suggestive of PJI include prosthesis with surrounding purulence and histopathologic examination of periprosthetic tissue demonstrating acute inflammation [5]. However, these findings are nonspecific and may be observed with alternative etiologies including metallosis and inflammatory arthritis. (See 'Differential diagnosis' below.)

For cases in which a definitive diagnosis of PJI cannot be made, additional data (including serum inflammatory markers and synovial fluid examination) may provide supportive evidence regarding the likelihood of infection (table 2):

● Routine serum inflammatory markers include erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) [1-3]. Less commonly used serum markers that may warrant further study include D- dimer, procalcitonin, and interleukin-6 [49]. (See 'Serum inflammatory markers' below.)

● Routine synovial fluid analysis consists of cell count with differential, Gram stain, aerobic and anaerobic culture, and crystal analysis [4,5,42]. Less commonly used synovial fluid markers that may warrant further study include alpha-defensin, leukocyte esterase, and CRP [50]. (See

'Synovial fluid analysis' below.)

Obtaining diagnostic studies

Initial evaluation — In the setting of suspected PJI, initial diagnostic evaluation consists of plain radiography (to evaluate for alternative causes of pain and instability) and measurement of serum inflammatory markers (ESR and CRP) [49]. (See 'Radiographic imaging' below and 'Serum inflammatory markers' below.)

Thereafter, diagnostic arthrocentesis should be performed, unless the diagnosis of PJI is evident clinically (eg, in the setting of a sinus tract) and definitive surgical debridement is planned [4,5,42]. If feasible, antimicrobial therapy should be withheld for at least two weeks prior to collecting specimens for culture [34].

Knee and shoulder joint aspiration often can be performed at the bedside; hip joint aspiration frequently requires guidance by ultrasound or fluoroscopy. If difficulty is encountered in obtaining synovial fluid, irrigation with sterile saline may be performed to obtain fluid for culture [51].

Synovial fluid should be sent for cell count with differential, Gram stain, aerobic and anaerobic culture, and crystal analysis [4,5,42]. Mycobacterial and fungal cultures should be submitted for patients with chronic, indolent, or refractory infection; previously culture-negative infection; or immunosuppression [2,52].

Synovial fluid may be sent for culture in a sterile tube (ideally a red-top tube with no additives and a tube with an anticoagulant such as ethylenediaminetetraacetic acid to guard against clotting) or in blood culture bottles. If blood culture bottles are used, synovial fluid also should also be sent in a sterile container for Gram stain. Use of blood culture bottles may increase the likelihood of recovering nonpathogenic skin contaminants; in such cases, culture results should be interpreted in the context of the Gram stain result. (See 'Microbiology studies' below and 'Synovial fluid analysis' below and "Septic arthritis in adults", section on 'Obtaining clinical specimens'.)

In patients with a sinus tract, drainage (collected by aspiration) should be sent for culture; swabs from the sinus tract should be not be sent given discordance with deep cultures [42,53]. In patients with fever or other systemic manifestations of infection, blood cultures (two sets) should be obtained.

Intraoperative evaluation — Intraoperative purulence may be attributable to PJI, in the absence of other causes; alternative etiologies include crystal-associated arthritis and metallosis. (See 'Differential diagnosis' below.)

Intraoperative specimens should consist of at least three periprosthetic tissue samples (ideally five, to minimize sampling error and optimize specificity) obtained with different instruments and put into separate sterile containers, to ensure that there is no cross-contamination between specimens. The samples should be sent for culture (aerobic and anaerobic) and frozen section histology; tissue Gram stain need not be sent routinely (it has high specificity but low sensitivity for diagnosis of PJI) [54-56].

Inoculation of periprosthetic tissues into blood culture bottles has been associated with higher sensitivity compared with cultures using conventional plates and broth media [57-59]. (See 'Microbiology studies' below and 'Histopathology' below.)

If pus is encountered, it should be aspirated in a sterile tube and sent for culture. Swab cultures should be avoided given low sensitivity [42].

Mycobacterial and fungal cultures should be submitted for patients with chronic, indolent, or refractory infection; previously culture-negative infection; or immunosuppression [2,52].

If the prosthesis is explanted, sonication (eg, to dislodge biofilm) may be performed, followed by culture of sonication fluid. (See 'Culture-negative infection' below.)

Interpreting test results

Microbiology studies — The microbiology of PJI is discussed above. (See 'Microbiology' above.)

The diagnosis of PJI may be established in the setting of two or more periprosthetic cultures with phenotypically identical organisms (a combination of preoperative synovial fluid aspiration culture and intraoperative tissue culture or ≥2 intraoperative tissue cultures) [4,5]. (See 'Clinical approach' above.)

A single positive culture with a virulent organism (such as S. aureus) may also represent PJI [60]. A single culture due to an organism of relatively low virulence (such as S. epidermidis, Corynebacterium spp, Cutibacterium spp, or Bacillus spp) is generally considered a contaminant. If the same organism is observed in multiple cultures, it may be presumed to represent a true pathogen; such cases should be evaluated in the context of other available evidence [1].

Synovial fluid culture has high sensitivity and specificity for diagnosis of PJI (72 and 95 percent, respectively, in one systematic review) [61]. The sensitivity of periprosthetic tissue culture is variable (65 to 94 percent) [42,62]. Use of saline irrigation to obtain cultures may reduce the culture specificity [63].

Sinus tract culture findings must be correlated with other data, since results may reflect skin flora contamination.

Synovial fluid analysis — Synovial fluid should be sent for cell count with differential, Gram stain, aerobic and anaerobic culture, and crystal analysis [4,5,42]. Less commonly used synovial fluid markers that may warrant further study include synovial fluid alpha-defensin, leukocyte esterase, and CRP [50].

For cases in which a definitive diagnosis of PJI cannot be made, synovial fluid analysis may be used (in conjunction with serum inflammatory markers) as supportive evidence regarding the likelihood of infection. (See 'Clinical approach' above.)

The approach to interpretation of synovial fluid analysis depends in part on the timing of clinical

presentation. In the setting of early-onset PJI, the synovial fluid cell count is often >10,000 cells/microL (>90 percent neutrophils). In the setting of delayed- and late-onset PJI, the synovial fluid cell count is often >3000 cells/microL (80 percent neutrophils).

The interpretation of synovial fluid markers in the context of other clinical factors has not been standardized; a number of criteria have been proposed (table 2) [4-8]. We favor the MSIS 2011 diagnostic criteria, which are used most widely. The ICM 2018 diagnostic criteria proposed a score- based definition for PJI with inclusion of synovial fluid parameters as minor criteria; however, these criteria include use of alpha-defensin and synovial fluid leukocyte esterase, which are not routinely available.

Cell count and polymorphonuclear leukocytes (PMN) thresholds have been observed to differ slightly between chronic total knee arthroplasty infection (1100 to 3000 cells/microL, 64 to 75 percent PMNs) and chronic total hip arthroplasty (THA) infection (745 to 3000 cells/microL, 74 to 80 percent PMNs) [43,63-68]. In a retrospective study including 337 patients with suspected PJI, the most accurate cell count threshold for patients with knee PJI was 1630 cells/microL (sensitivity and specificity 84 and 82 percent, respectively) with 60 percent neutrophils (sensitivity and specificity 80 and 77 percent, respectively) [69]. The most accurate cell count threshold for patients with hip PJI was 2582 cells/microL (sensitivity and specificity 80 and 85 percent, respectively) with 66 percent neutrophils (sensitivity and specificity 82 percent). Use of saline irrigation to obtain synovial fluid may confound the cell count.

Synovial fluid alpha-defensin may be useful for diagnosis of PJI. In one prospective study including 156 patients with suspected PJI, the sensitivity, specificity, positive predictive value, and negative predictive value were 97, 97, 88, and 99 percent, respectively [70] (based on the 2014 International Consensus Group definition) [6]. An lateral flow assay for measurement of synovial fluid alpha-defensin (Synovasure lateral flow test) was approved by the United States Food and Drug Administration in 2019; however, it uncertain whether this test is more useful for prediction of PJI than cell count with differential. In a meta-analysis including 10 studies and more than 750 patients with suspected PJI, the sensitivity and specificity of the test for diagnosis of PJI were 78 and 91 percent, respectively [71].

Serum inflammatory markers — Routine serum inflammatory markers include ESR and CRP [1-3]; less commonly used serum markers that may warrant further study include D-dimer, procalcitonin, and interleukin-6 [49].

For cases in which a definitive diagnosis of PJI cannot be made, serum inflammatory markers may be used (in conjunction with synovial fluid analysis) as supportive evidence regarding the likelihood of infection. (See 'Clinical approach' above.)

The approach to interpretation of serum inflammatory markers depends in part on the timing of clinical presentation. In the setting of early-onset PJI, ESR is not useful; CRP is often >100 mg/L. In the setting the setting of delayed and late onset PJI, ESR is often >30 mm/hour and CRP is often >10 mg/L.

The interpretation of serum inflammatory markers in the context of other clinical factors has not been standardized; a number of criteria have been proposed (table 2) [4-8]. We favor the MSIS 2011 diagnostic criteria, which are used most widely.

Following joint replacement surgery, the CRP may require two to three weeks to return to normal preoperative values, and the ESR may require up to a year to return to normal preoperative values [72]. Serum inflammatory markers must also be interpreted with caution in the setting of coexistent chronic inflammatory disease, which can also elevate serum inflammatory markers.

In a meta-analysis including 30 studies and more than 3900 revision arthroplasties, sensitivity and specificity of ESR and CRP for diagnosis of PJI were 75 and 88 percent and 70 and 74 percent, respectively [49]. Combined use of ESR and CRP has been associated with sensitivity of 96 percent [66,73]; if both tests are negative, the likelihood of PJI is low. However, PJI may be present in the setting of normal ESR and CRP; factors associated with such cases include infection due to pathogens of low virulence, prior antibiotic use, and immunosuppression [3].

Radiographic imaging — Radiographic imaging may be of value but usually does not provide a definitive diagnosis of PJI. In general, plain radiographs should be performed in the setting of suspected PJI; these are useful to screen for prosthetic loosening and fracture but lack sensitivity and specificity for diagnosis of PJI [2].

The following plain radiography findings may be observed in the setting of PJI: abnormal lucency larger than 2 mm in width at the bone-cement interface, changes in the position of prosthetic components, cement fractures, periosteal reaction, or motion of components on stress views [74]. These findings are correlated with the duration of infection; three to six months may be required before manifestation of such changes. In addition, these changes are not specific for infection; they are also seen frequently with aseptic processes.

Other studies such as leukocyte scans, positron emission tomography (PET) scans, computed tomography (CT) scans, magnetic resonance imaging (MRI) scans, or bone scans are not useful for routine diagnostic evaluation in most cases of suspected PJI [5].

Scintigraphy (such as technetium-colloid scans or gallium-67 labeled white blood cell scans) is rarely useful in early infection; scans may be falsely abnormal for up to 12 months following surgery due to periprosthetic bone remodeling [75]. In addition, technetium-colloid scans can be positive in the setting of aseptic loosening. A normal scintigraphy study can be considered evidence against the presence of infection (high sensitivity), but a positive study is not definitive for establishing the diagnosis of PJI (low specificity).

Fluorodeoxyglucose-positron emission tomography (FDG-PET) is not useful within the first year of arthroplasty due to false-positive results associated with postoperative inflammation [76]. In a systematic review including 11 studies evaluating the diagnostic utility of PET for imaging patients with suspected PJI, the pooled sensitivity and specificity of FDG-PET was 82 and 86 percent, respectively

[77]. The accuracy of PET scan was higher in THA infection and when criteria for PJI were predetermined.

Use of CT scan is limited by imaging artifacts caused by metallic implants, and MRI can be performed only with implants that are safe for this modality, such as those composed of titanium or tantalum [42]. Some MRI scanners have metal suppression modalities (Metal Artifact Reduction Sequence) that permit greater resolution and an improved recognition of prosthesis failure, with or without infection [76].

Histopathology — Histopathologic examination of periprosthetic tissue may be performed to evaluate for infiltration of polymorphonuclear cells, indicative of an acute inflammatory reaction supporting a diagnosis of PJI. This is often done as a frozen section; it may also be done via standard histopathologic examination. The threshold number of PMNs per high-power field (HPF; 400x magnification) to distinguish PJI from aseptic failure is uncertain; a threshold of at least five PMNs per HPF has been used (sensitivity and specificity >80 percent and >90 percent, respectively) [1-3]. In one meta-analysis, histopathology had a pooled diagnostic odds ratio of 54.7 (95% CI 31.2-95.7) for diagnosis of PJI [55]; however, sensitivity of the test is limited (18 to 67 percent) [78-83].

Culture-negative infection — For patients with suspected PJI and negative cultures from synovial fluid and periprosthetic tissue, repeat joint aspiration should be attempted. If feasible, antimicrobial therapy should be withheld for at least two weeks prior to collecting specimens for culture. In addition to aerobic and anaerobic cultures, mycobacterial and fungal cultures should be submitted [2,52]. In the setting of suspected delayed-onset PJI, extended culture incubation (at least 14 days) may increase culture sensitivity (especially for recovery of Cutibacterium spp) [84,85].

Additional tools for diagnosis of culture-negative PJI include explant sonication, molecular diagnostic testing, and serologic testing.

Sonication of an explanted prosthesis can improve the yield of microbiologic diagnosis compared with tissue culture, especially in the setting of perioperative antibiotics [86,87]. In one meta-analysis including 12 studies, pooled sensitivity and specificity were 80 and 95 percent, respectively [87]. Sonication is not routinely available in many microbiology laboratories; vortexing an explanted prosthesis is a reasonable alternative [88].

Nucleic acid amplification tests may be useful when routine cultures are negative and clinical suspicion for PJI is high [89-94]. Many of these assays are based on detection of 16S rRNA gene(s) using a variety of polymerase chain reaction (PCR) techniques to evaluate sonicate fluid, synovial fluid, and joint tissue [95]. The results must be interpreted carefully and correlated with Gram stains and clinical and epidemiologic findings, since small amounts of contaminating bacterial material can lead to a false- positive result [92]. Metagenomic shotgun sequencing is a novel method under development for extracting, sequencing, and identifying nucleic acid as an alternative to PCR [96].

In the setting of relevant epidemiologic risk factors for infection due to C. burnetii or Brucella spp (eg, travel history, environmental or animal exposure), serologic tests to evaluate for infection due to these

organisms should be performed. (See "Clinical manifestations and diagnosis of Q fever" and "Brucellosis: Epidemiology, microbiology, clinical manifestations, and diagnosis".)

DIFFERENTIAL DIAGNOSIS

PJI must be differentiated from mechanical and aseptic problems:

● Aseptic loosening – Hardware loosening occurs due to wear of the prosthetic components. Persistent joint pain is suggestive of infection, whereas pain with joint motion and weight bearing (which abates with rest) is suggestive of hardware loosening. (See "Complications of total hip arthroplasty", section on 'Aseptic loosening'.)

● Dislocation – Dislocation refers to an injury that forces the prosthesis out of position. Clinical manifestations include pain, difficulty moving the joint, and deformity of the joint area. Uncommonly, dislocation can occur in the setting of PJI, most frequently in the setting of late-onset infection. The presence of dislocation is established radiographically. (See "Complications of total hip arthroplasty", section on 'Dislocation'.)

● Gout and pseudogout – Gout (monosodium urate crystal deposition disease) and pseudogout (calcium pyrophosphate crystal deposition [CPPD] disease) are characterized by severe pain, erythema, edema, and warmth. The diagnosis of gout is established by visualization of uric acid crystals in synovial fluid; the diagnosis of pseudogout is established by visualization of CPPD crystals in synovial fluid. (See "Clinical manifestations and diagnosis of gout" and "Clinical manifestations and diagnosis of calcium pyrophosphate crystal deposition (CPPD) disease".)

● Hemarthrosis – Hemarthrosis refers to bleeding into a joint due to traumatic or nontraumatic causes. It is characterized by pain, swelling, warmth, and impaired mobility; the diagnosis is established by joint aspiration. (See "Overview of hemarthrosis".)

● Osteolysis – Osteolysis refers to bone resorption as a biologic response to particulate debris due to wear of the prosthetic components. The diagnosis is established radiographically. (See "Complications of total hip arthroplasty", section on 'Osteolysis and wear'.)

● Metallosis – Metallosis refers to reactive synovitis to metallic debris. Synovial fluid cell counts may be elevated in this condition, but the neutrophil percentage is usually below the threshold for diagnosis of PJI. (See "Complications of total hip arthroplasty".)

SOCIETY GUIDELINE LINKS

INFORMATION FOR PATIENTS

● Beyond the Basics topic (see "Patient education: Joint infection (Beyond the Basics)")

SUMMARY

● Prosthetic joint infection (PJI) is a serious complication of prosthetic joint implantation. The rate of PJI is highest during the first two years following surgery. The rate of PJI ranges between 0.5 to 2 percent for knee replacements, 0.5 to 1.0 percent for hip replacements, and <1 percent for shoulder replacements. The higher rate of PJI in knee arthroplasties may be attributable to greater mobility in the joint and soft tissue and less protective soft tissue coverage. (See 'Epidemiology' above.)

● PJIs may be categorized as early onset (<3 months after surgery), delayed onset (3 to 12 months after surgery), and late onset (>12 months after surgery). The timing of infection can be a clue as to the mechanism of infection and the identity of the infecting organism. However, these definitions are controversial and not always clear-cut, particularly in patients for whom the diagnosis is delayed. (See 'Definitions' above and 'Microbiology' above.)

● The clinical manifestations of PJI depend on the timing of symptom onset (see 'Clinical manifestations' above):

• Patients with early-onset infection may present with hematoma formation or superficial necrosis of the incision. One or more of the following findings may be observed: joint pain, warmth, erythema, induration, or edema at the incision site, wound drainage or dehiscence, joint effusion, and fever.

• Patients with delayed-onset infection typically present with an indolent course characterized by persistent joint pain, with or without early implant loosening. Fever is present in less than half

of cases. Sinus tract associated with intermittent drainage may be observed; in the absence of a sinus tract, physical exam findings are often minimal.

• Patients with late-onset infection typically present with acute onset of systemic symptoms associated with bacteremia, together with joint pain in a previously well-functioning joint.

● PJI should be suspected patients with a joint prosthesis and relevant signs and symptoms of infection (including joint pain, warmth, erythema, induration, or edema at the incision site, sinus tract or persistent wound drainage, wound dehiscence, joint effusion, or fever). The diagnosis of PJI can be challenging because the definition is not standardized; a number of diagnostic criteria have been proposed (table 2). (See 'Clinical approach' above.)

● The diagnosis of PJI may be established in any of the following circumstances (see 'Clinical approach' above):

• Presence of a sinus tract that communicates with the prosthesis

• Two or more periprosthetic cultures with phenotypically identical organisms (≥2 intraoperative cultures or a combination of preoperative synovial fluid aspiration culture and intraoperative tissue culture)

● In the setting of suspected PJI, initial diagnostic evaluation consists of plain radiography (to evaluate for alternative causes of pain and instability) and measurement of serum inflammatory markers (erythrocyte sedimentation rate and C-reactive protein). Thereafter, diagnostic arthrocentesis should be performed (unless a sinus tract is present and definitive debridement is planned). Synovial fluid should be sent for cell count with differential, Gram stain, aerobic and anaerobic culture, and crystal analysis. In patients with a sinus tract, drainage (collected by aspiration) should be sent for culture. In patients with fever or other systemic manifestations of infection, blood cultures (two sets) should be obtained. Intraoperative specimens should consist of at least three periprosthetic tissue samples (ideally five); if pus is encountered, it should be aspirated in a sterile tube and sent for culture. (See 'Obtaining diagnostic studies' above.)

● For cases in which a definitive diagnosis of PJI cannot be made, additional data (including serum inflammatory markers and synovial fluid examination) may provide supportive evidence regarding the likelihood of infection. The approach to interpretation of synovial fluid analysis depends in part on the timing of clinical presentation. The interpretation of synovial fluid parameters in the context of other clinical factors has not been standardized; we favor the Musculoskeletal Infection Society 2011 diagnostic criteria, which are used most widely (table 2). (See 'Clinical approach' above and 'Synovial fluid analysis' above.)

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