osteomyelitis

3

Best Practice & Research Clinical RheumatologyVol. 20, No. 6, pp. 1065e1081, 2006

doi:10.1016/j.berh.2006.08.014available online at http://www.sciencedirect.com

Osteomyelitis

Irene G. Sia MD

Assistant Professor of Medicine and Consultant in Infectious Diseases

Elie F. Berbari* MD

Assistant Professor of Medicine and Consultant in Infectious Diseases

Section of Orthopedic Infectious Diseases, Mayo Clinic College of Medicine,

200 First St SW, Rochester, MN 55902, USA

Osteomyelitis can result from hematogenous or contiguous microbial seeding of the bone.Staphylococcus aureus is the most common infecting microorganism. Although any bone can po-tentially develop osteomyelitis, long-bone, vertebral, and foot osteomyelitis account for the ma-jority of cases. Confirmatory diagnosis of osteomyelitis often depends on the results of a bonebiopsy and bone cultures. Radiologic and laboratory studies are often helpful in leading to thediagnosis, determining the extent of the disease, and following up selected patients with osteo-myelitis. Optimal therapy for osteomyelitis requires the collaboration of a multidisciplinary teamof physicians. Debridement is often needed in contiguous osteomyelitis, whereas acute hema-togenous and vertebral osteomyelitis can often be treated with a prolonged course of anti-microbial therapy.

Key words: osteomyelitis; Staphylococcus aureus; antimicrobial therapy; debridement.

Osteomyelitis is a disease which is heterogeneous in its pathophysiology, clinical pre-sentation, and management. It is felt to be one of the most difficult-to-treat infectiousdiseases. Progressive bony destruction and the formation of sequestra are hallmarks ofosteomyelitis. Osteomyelitis can result from hematogenous seeding, contiguousspread of infection, or direct inoculation of microorganism(s) into intact bone.

Several systems for classification of osteomyelitis have been described. The twomajor classification schemes are those by Waldvogel et al1 and Cierny et al.2 In theWaldvogel scheme, osteomyelitis is classified according to the duration of the disease(acute or chronic), the mechanism of infection (hematogenous or contiguous), and thepresence of vascular insufficiency. The CiernyeMader classification of osteomyelitis is

* Corresponding author. Tel.: þ1 507 2556482; Fax: þ1 507 2557767.

E-mail address: [email protected] (E.F. Berbari).

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1066 I. G. Sia and E. F. Berbari

based on the portion of bone affected, the physiologic status of the host, and otherrisk factors (Table 1). This classification can be of clinical value in the treatment andprognosis of osteomyelitis.

Optimal management of osteomyelitis depends on its pathophysiology, microbiol-ogy and host immune factors. Because of these differences, long-bone osteomyelitis,osteomyelitis due to open fractures, vertebral osteomyelitis, osteomyelitis in patientswith diabetes mellitus and peripheral vascular insufficiency, and non-infectious oste-omyelitis e e.g. SAPHO (synovitis, acne, plantar pustulosis, hyperostosis and osteitis)syndrome e will be discussed separately. Special sections on unusual sites of oste-omyelitis, osteomyelitis in patients with rheumatoid arthritis, and culture-negativeosteomyelitis are also included. Diagnosis of osteomyelitis generally involvesa bone biopsy. Definitive treatment often requires combined surgical and medicalapproaches.

CLINICAL FORMS OF OSTEOMYELITIS

Long-bone osteomyelitis

Long-bone osteomyelitis can result from hematogenous spread or contiguous to a soft-tissue infection. Hematogenous osteomyelitis is almost always a monomicrobial infec-tion, with Staphylococcus aureus being the most prevalent causative microorganism.3,4

Coagulase-negative staphylococci, aerobic gram-negative bacteria, and Peptostreptococ-cus spp are also frequently isolated (Table 2).5 The microbiology of osteomyelitis in

Table 1. The CiernyeMader staging system for osteomyelitis.

Anatomic type

Stage 1: Medullary osteomyelitis

Stage 2: Superficial osteomyelitis

Stage 3: Localized osteomyelitis

Stage 4: Diffuse osteomyelitis

Physiologic class

A host: normal host

B host: systemic compromise (Bs)

Local compromise (Bi)

Systemic and local compromise (Bis)

C host: treatment worse than the disease

Systemic or local factors that affect immune surveillance, metabolism, and local

vascularity

Systemic (Bs) Local (Bi)

Malnutrition Chronic lymphedema

Renal, hepatic failure Major vessel compromise

Diabetes mellitus Small vessel disease

Chronic hypoxia Vasculitis

Immune disease Venous stasis

Malignancy Extensive scarring

Extremes of age Radiation fibrosis

Immunosuppression Neuropathy

Tobacco abuse

Osteomyelitis 1067

special groups of individuals is summarized in Table 3. Adults usually have vague symp-toms consisting of non-specific pain and low-grade fever, and a subacute to chronicpresentation. Fever, chills, local swelling and erythema over the involved bone areoccasionally seen. The source of bacteremia may be a trivial skin infection or a moreserious infection such as bacterial endocarditis. Hematogenous long-bone osteomyeli-tis is a well-known complication in injection drug users in whom multifocal involvementis common.6 Patients with contiguous-focus osteomyelitis often present with localizedbone pain, erythema, swelling and drainage around the area of wound infection. Bothhematogenous and contiguous-focus osteomyelitis can progress to a chronic condition.Chronic osteomyelitis usually presents with chronic pain and drainage; fever, if present,is typically low-grade.

The diagnosis of osteomyelitis is first suspected on clinical grounds. The leukocytecount may be elevated, but is often normal in chronic cases. Both erythrocyte sedimen-tation rate (ESR) and C-reactive protein (CRP) are elevated, and usually return to nor-mal during the course of treatment. Confirmation of the presence of osteomyelitisusually entails a combination of radiologic, microbiologic, and histopathologic tests.Cross-sectional imaging modalities such as computed tomography (CT) scanning andmagnetic resonance imaging (MRI) are now considered standard in the diagnosis of os-teomyelitis.7 Although expensive, they are sensitive and specific. These modalities giveexcellent anatomic delineation of the infection and the surrounding soft tissue. CT scanshelp to identify areas of necrotic bone and soft-tissue extension; however, when a metalis present in or near the area of osteomyelitis, there is substantial loss of image resolu-tion.7 MRI provides excellent resolution and delineation of bone and soft tissues. How-ever, metallic implants may produce local artifacts, decreasing image quality. Nuclear

Table 2. Microbiology of osteomyelitis.

1. Common

� Staphylococcus aureus

� Coagulase-negative staphylococci

� Streptococci

� Enterococci

� Pseudomonas sp

� Enterobacter sp

� Proteus sp

� Escherichia coli

� Serratia sp

� Anaerobes (Peptostreptococcus sp, Clostridium sp, Bacteroides fragilis group)

II. Less common

� Mycobacterium tuberculosis

� Mycobacterium avium complex

� Rapidly growing mycobacteria

� Dimorphic fungi

� Candida sp

� Aspergillus sp

� Mycoplasma sp

� Tropheryma whippelii

� Brucella sp

� Salmonella sp

� Actinomycetes

ups.

Etiology

Staphylococcus aureus

Enterobacteriacae, Group B streptococci

Salmonella sp, Staphylococcus aureus

Staphylococcus aureus, Pseudomonas aeruginosa, Candida sp

Haemophilus influenzae group B

Staphylococcus aureus

Aerobic gram-negative bacilli, Enterococcus sp

Pseudomonas aeruginosa, Staphylococcus aureus

Coagulase-negative staphylococci, Staphylococcus

aureus, aerobic gram-negative bacilli

Candida sp

Mycobacterium tuberculosis, Brucella sp

Polymicrobial: Staphylococcus aureus,

b-hemolytic streptococci, enterococci,

aerobic gram-negative bacilli

Clostridium sp, Bacillus sp, Stenotrophomonas maltophilia,

Nocardia sp, atypical mycobacteria, Aspergillus sp,

Rhizopus sp, Mucor sp

Staphylococcus aureus, coagulase-negative staphylococci

Pasteurella multocida

Pseudomonas aeruginosa

Actinomyces sp

ine vaccination of children.

1068

I.G

.Sia

and

E.F.

Berb

ari

Table 3. Osteomyelitis in special gro

Mechanism Special groups

Hematogenous osteomyelitis Common in children and adults

Neonates

Sickle-cell disease

Injection drug users

Infants and childrena

Vertebral osteomyelitis Most common in adults

Urinary tract infection

Injection drug users

Following spine surgery

Infections of intravascular devices

In endemic regions

Contiguous-focus osteomyelitis Diabetes mellitus, vascular

insufficiency, or following a

contaminated open fracture

Soil contamination

Orthopedic fixation devices

Cat bites

Following puncture injuries on the

foot by nails or other sharp objects

Following periodontal infection

a The incidence of invasive disease caused by Haemophilus influenzae B is decreasing due to rout

Osteomyelitis 1069

bone scans, although sensitive, are expensive and sometimes non-specific. White cellslabeled with technetium-99m-labeled methylene diphosphonate (99mTc-MDP), 67gal-lium citrate (67Ga) or 111indium-oxyquinoline (111In) are commonly used as tracersfor evaluation of osteomyelitis. Three-phase technetium bone scan is preferred if theplain films are normal.8 However, degenerative joint disease, non-infectious inflamma-tory bone disease, bone tumor, and recent surgery can give false-positive results. Plainfilms are insensitive but fairly specific, inexpensive, and readily available; abnormalitiesare usually seen 10e14 days following onset of the infection. The experience with pos-itron emission tomography (PET) scanning for the diagnosis of osteomyelitis is limited.

The confirmatory diagnosis of long-bone osteomyelitis depends on the isolation ofthe causative microorganism(s) in cultures of bone specimens, blood or joint fluid. Ifpossible, cultures should be obtained before antimicrobials are initiated. Identificationof the causative microorganism(s) and in-vitro susceptibility data will help optimize sur-gical and medical therapy (Table 4). This is usually done by surgical sampling or by needleaspiration under radiologic guidance. Culture of bone biopsies yields a microbiologicdiagnosis in 94% of cases.4 Swab cultures from draining wounds and sinus tracts arenot reliable for predicting organisms that will be isolated from infected bone5,9, butmight be helpful in guiding infection control measures.

Most cases of long-bone osteomyelitis in adults require a combination of adequatesurgical debridement and specific antimicrobial therapy for successful eradication of theinfection. Surgical management of osteomyelitis follows certain principles (Table 5).Appropriate management of dead space may include avascularized bone graft, placementof cancellous bone grafts, or temporary use of antibiotic-impregnated acrylic beads.External or internal fixation with plates, screws, and/or rods is required in some patientsto achieve skeletal stability. Antimicrobials should be withheld if possible until deep cul-tures have been obtained during debridement or by means of a bone biopsy. Therapy isusually initiated with a parenteral antimicrobial regimen to cover clinically suspectedpathogens (Table 4); treatment may be modified once the microorganism has been iden-tified and drug susceptibility results have become available.

The optimal duration of antimicrobial therapy in osteomyelitis is unknown. Manyexperts advocate a total duration of 4e6 weeks of parenteral therapy.3,10 This is pri-marily based on the results of experimental animal studies showing that 4 weeks oftherapy was more effective in sterilizing the bone than 2 weeks.11. Furthermore, ittakes up to 6 weeks for the debrided bone to be covered by vascularized soft tissue.Most patients continue outpatient parenteral therapy with a long-term intravenouscatheter such as a peripherally inserted central catheter.12 Oral therapy using drugswith excellent bioavailability e such as fluoroquinolone, clindamycin, co-trimoxazole,metronidazole, fluconazole, and linezolid e may be considered in select patients.13

The availability of antimicrobials with increased antimicrobial activity and enhancedoral bioavailability has improved the treatment of osteomyelitis. However, the greatestadvances in therapy have been in improvements in surgical debridement, soft tissuecoverage and stabilization procedures.14

Open-fracture osteomyelitis

Open contaminated fractures can lead to the development of osteomyelitis of the frac-tured bone in 3e25% of cases, depending on fracture type, degree of soft-tissue injury,degree of microbial contamination, and whether systemic and/or local antimicrobialtherapies have been administered.15e19 Osteomyelitis can also arise as a nosocomial


Table 4. Antimicrobial therapy for selected microorganisms in adults with chronic osteomyelitis.

Microorganisms First choice alternative choice

Staphylococci,

oxacillin-sensitive

Nafcillin sodium or oxacillin

sodium, 1.5e2.0 g intravenously

every 4 h for 4e6 weeks

or

Cefazolin 1e2 g intravenously


Vancomycina, 15 mg/kg

intravenously every 12 h

for 4e6 weeks

Staphylococci,

oxacillin-resistant



for 4e6 weeks

Linezolid 600 mg orally or

intravenously every 12 h for 6 weeks

or

Levofloxacinb 500e750 mg orally

or intravenously daily and oral rifampin

600 mg daily for 6 weeks

Penicillin-sensitive

streptococci

Aqueous crystalline penicillin G,

20� 106 U/24 h intravenously,

either continuously or in six

equal divided daily doses for

4e6 weeks

or

Ceftriaxone 1e2 g intravenously

or

intramuscularly every 24 hours

for 4e6 weeks

or

Cefazolin 1e2 g intravenously




for 4e6 weeks

Enterococci or

streptococci with

penicillin

MIC� 0.5 mg/mL

or nutritionally

variant streptococci

Aqueous crystalline penicillin G,

20� 106 U/24 h intravenously,

either continuously or in six

equal divided daily doses for

4e6 weeks

or

Ampicillin sodium 12 g/24 h

intravenously either continuously

or in six equal divided daily doses

Optional: add gentamicin sulfate,

1 mg/kg intravenously

or intramuscularly



intravenously every 12 h for 4e6 weeks

Optional: add gentamicin sulfate, 1 mg/kg

intravenously or intramuscularly


Enterobacteriacae Ceftriaxone 2 g intravenously


Ciprofloxacinb 50e750 mg

orally every 24 h for 4e6 weeks

Pseudomonas

aeruginosa

or

Enterobacter sp.

Cefepime 2 g intravenously


or

Meropenem 1 g intravenously


Ciprofloxacina 750 mg orally every

12 h for 4e6 weeks

or

Ceftazidime 2 g intravenously every 8 h

MIC, minimum inhibitory concentration.a Dose based on normal creatinine clearance.b Should be avoided, if possible, in the pediatric population and in osteomyelitis associated with

fractures.

Osteomyelitis 1071

infection after treatment of an open fracture. Patients with open fractures are usuallyyoung males in the second or third decades of life. The tibia is the most frequent siteof post-traumatic osteomyelitis. Bacteria are inoculated directly on the bone surface atthe time of trauma, at the time of surgery, and/or in the early postoperative period;early microbial contamination can eventually lead to the development of osteomyelitisat the fracture site. Untreated, infection will ultimately lead to non-union, chronicosteomyelitis or amputation.

Post-traumatic osteomyelitis is often a polymicrobial infection.20 Pathogens can in-clude normal skin flora that contaminated the wound, microorganisms from the con-taminated soil, or nosocomial pathogens. Staphylococci and gram-negative aerobic andanaerobic bacilli are most frequently isolated (Table 3). Other microorganisms e suchas enterococci, fungi, and atypical mycobacteria e have been implicated as well. Signsand symptoms of infection typically appear several months following the injury. Pa-tients may present with localized bone pain, erythema, swelling, drainage or woundinfection. The hallmarks of open-fracture osteomyelitis, however, are persistentnon-union of the fracture site and poor wound healing following wound closure orsoft tissue coverage. Other symptoms such as local erythema, fever, and chills are fre-quently absent. Diagnosis is suspected clinically and confirmed by isolation of the path-ogens from biopsy specimens. However, cultures at the time of presentation or firstdebridement are not useful21; cultures of bone biopsies after the initial debridementare helpful and important in guiding therapy. Radiographic changes may be subtle.111In-labeled leukocyte scan may be obtained to help determine the presence and ex-tent of osteomyelitis at sites of fracture non-union when hardware is present. CT scanmay be useful in determining the surgical approach; MRI provides a more accurate im-age of the extent of infection.22

Post-traumatic osteomyelitis is a difficult infection to treat. Surgical management isidentical to the management of long-bone osteomyelitis. A delay of 5 hours in surgicaldebridement has been associated with a higher incidence of infection.23 The use of ex-ternal versus intramedullary fracture fixation devices in contaminated open fractures iscontroversial. Parenteral prophylactic antimicrobial therapy should be administeredwithin 6e8 hours after trauma24, modified on the basis of culture and susceptibilityresults, and continued for 7e10 days. Management of established osteomyelitis follow-ing open fractures requires debridement of the surgical site, identification of the caus-ative microorganism(s), and pathogen-directed antimicrobial therapy (Table 4). Ifforeign bodies are retained, chronic oral antimicrobial suppression until bone fusionmay be helpful. The use of a quinoloneerifampin combination for 3 months for infec-tion of a fracture fixation device with susceptible staphylococci has a reported successrate in eradicating the infection of more than 80%.25,26 However, given the potentialnegative effect of quinolones on bone healing27, we have not adopted this antimicrobial

Table 5. Surgical principles in osteomyelitis.

Complete drainage of infected tissue

Thorough debridement of necrotic tissue

Removal of all hardware

Elimination of dead space

Complete soft tissue coverage

Bone/fracture stabilization


regimen in our practice. Definitive therapy with removal of the foreign body andpathogen-directed antimicrobial therapy could be undertaken without compromisinglimb function in patients with recurrent infections after bone healing and discontinu-ation of chronic oral antimicrobial suppressive therapy.28

The administration of prophylactic parenteral antimicrobials is effective in the pre-vention of osteomyelitis in patients with open contaminated fractures.29,30 However,prolonged prophylactic systemic antimicrobial use does not prevent the risk of infec-tion and can potentially lead to the development of resistant microorganisms.31 Clin-ical studies evaluating local therapy with antibiotic-impregnated polymethylmethacrylate (PMMA) beads in the prevention and treatment of open fractures haveyielded favorable results, with lower fracture infection rates.19,32 Local antibiotic ther-apy also seemed to be effective in treating patients with infected non-union.30,33 Over-all, existing studies suggest that local delivery of antibiotic is a useful adjunctivetreatment of open-fracture osteomyelitis. Hyperbaric oxygen may be useful in selectedpatients.34,35

Vertebral osteomyelitis (spondylodiscitis)

In the majority of cases, infection of the intervertebral disc and the adjacent vertebraeis hematogenous in origin. Sources of infection include skin and soft tissue, infectiveendocarditis, infected intravenous sites, intravenous drug abuse, the oral cavity, andthe respiratory, gastrointestinal and genitourinary tracts.36,37 In many cases, however,the primary site of infection cannot be identified.38 Infection occurs via the segmentalarterial circulation of the vertebrae.39 The lumbar vertebral bodies are most often in-volved; the infection then spreads by direct extension through the endplate into thedisc. Posterior and anterior extension may lead to abscesses in the epidural, subdural,paravertebral, mediastinal, retroperitoneal, or psoas spaces. Disc space infection andcontiguous vertebral osteomyelitis can also develop as result of direct inoculationfrom trauma or as a complication of spinal surgery.

S. aureus and coagulase-negative staphylococci are the most common microorgan-isms encountered in vertebral osteomyelitis. Gram-negative aerobic bacilli and Candidasp are more commonly seen in intravenous drug abusers and immunosuppressed pa-tients and in the postoperative setting (Table 3). Spondylodiscitis caused by Mycobac-terium tuberculosis and Brucella sp is common in endemic regions. In approximately onethird of patients, a causative microorganism cannot be identified.40 The majority of pa-tients present with localized insidious pain and tenderness in the spine; fever is presentin less than half of the cases. Motor and sensory deficits due to compression of thespinal cord or nerve root are present in up to 15% of patients.41e45 Patients with ad-vanced infection of the lumbar spine, especially in tuberculosis, may present with pain-ful gibbus or psoas abscess.

Diagnosis requires a high index of suspicion in at-risk patients presenting with com-patible signs and symptoms. The goal of the diagnostic evaluation is to identify the or-ganism and to determine the extent of infection. Neurologic function and spinal stabilityshould always be carefully assessed. Plain radiographs are insensitive and non-specific;CT findings are often non-specific. Gadolinium-enhanced MRI is currently the imagingof choice for evaluation of suspected vertebral osteomyelitis; it is sensitive, specific, andaccurate.7,46 A three-phase bone scan is sensitive and specific in early stages of infec-tion.47 67Gallium citrate scan is the most sensitive and specific radionuclide test for ver-tebral osteomyelitis and may be useful in monitoring response to treatment. It is

Osteomyelitis 1073

suggested that fluorodeoxyglucose PET may be the most sensitive test with greaterspecificity than leukocyte scintigraphy for detecting chronic axial osteomyelitis48; how-ever, this is of limited availability. CT-guided percutaneous needle biopsy is often neces-sary to confirm the diagnosis. Cultures of spinal specimens are positive in up to 52% ofcases.49 If the first aspirate is negative, repeat aspiration with a larger needle needs tobe performed. Open biopsy should be reserved for patients with a non-diagnostic per-cutaneous biopsy, in patients not responding to empiric antimicrobial therapy, or whena non-infectious etiology is in the differential diagnosis.

The goals of therapy for vertebral osteomyelitis include eradication of the infection,relieving pain, preserving or restoring neurologic function, and maintaining spinal sta-bility. Complete bed rest is often not necessary. The spine could be stabilized witha corset or a body brace. Parenteral antimicrobial therapy directed at the pathogenis routinely continued for a minimum of 4e6 weeks; longer therapy may be necessaryfor patients with extensive bone destruction and/or paravertebral infection. Open sur-gical therapy is not necessary in the majority of cases. Surgical debridement should beconsidered in patients with large paravertebral or epidural abscesses associated withspinal cord compromise, when medical management fails, or when the spine is me-chanically unstable. In selected cases, percutaneous transpedicular debridement anddiscectomy performed under fluoroscopic guidance in the early stages of infectionmay prevent the progression of bone destruction and deformity.50 The neurologicalstatus of the patient must be closely monitored. With effective antimicrobial therapy,spontaneous bony fusion occurs in l2e24 months.

Early postoperative hardware-associated spine infection is initially treated with sur-gical debridement and retention of the hardware; removal of spinal hardware may com-promise the stability of the spine and the spinal cord. In this setting, surgical debridementis followed by a course of parenteral antimicrobial therapy tailored to the specific path-ogen(s) (Table 4). This is typically followed by the use of chronic oral antimicrobial sup-pression until radiological evidence of bony fusion is achieved. Complete boneremodeling and fusion will typically be complete after 2 years. At that time, chronicoral suppression may be discontinued, with a risk, albeit low, of recurrence. If recur-rence occurs, spinal hardware is removed without compromising spine stability.

Several studies have now established the efficacy of antimicrobial prophylaxis priorto spine surgery in reducing the risk of postoperative superficial or deep infection, in-cluding vertebral osteomyelitis.51

The follow-up of patients with vertebral osteomyelitis relies on improvement inclinical parameters, inflammatory markers, and MRI findings. A drop in the ESR by25% of the baseline value is typically seen at 4e6 weeks of therapy, and is associ-ated with a low risk for relapse.52 MRI after 4e6 weeks of therapy typically showsresolution of soft-tissue changes but not bony changes; the absence of improve-ment in inflammatory markers or in MRI changes is associated with a higher relapserate.53

Osteomyelitis in patients with diabetes mellitus or vascular insufficiency

Foot infections and osteomyelitis in diabetics are associated with substantial morbidity,mortality, and excess care costs.54e56 Diabetes patients develop foot ulcers at anannual incidence close to 2%; of these, 15% will develop osteomyelitis and 16% willrequire amputation.54 Furthermore, recurrent infections occur in up to 36% of pa-tients.12 Several factors put diabetics at high risk for foot infections. Sensory, motor


and autonomic neuropathies, vascular insufficiency, and hyperglycemia lead to a varietyof consequences that ultimately result in the appearance of a non-healing ulcer andsubsequent development of contiguous osteomyelitis. Early recognition and optimalmanagement of these factors is important to the prevention or delaying the onsetof osteomyelitis (Table 6). It is recommended that all patients with diabetes mellitusshould have a complete foot examination performed yearly by a health-careprofessional.57,58

The clinical features of acute osteomyelitis in diabetic patients are often identical tothe clinical features of superficial foot infections. Up to two-thirds of diabetic foot in-fections are associated with osteomyelitis, especially if soft-tissue infection has beenpresent for more than 2 weeks.59,60 Osteomyelitis is more likely with ulcers thatare large (>2 cm), deep (>3 mm), and associated with exposed bone.60 In the majorityof cases infections are mixed, with both aerobic and anaerobic microorganisms(Table 3).61,62

The ability to probe a bony structure beneath an ulcer is highly sensitive for thepresence of osteomyelitis.59 In-labeled leukocyte scan can be helpful in the evaluationof diabetic patients with foot ulcers that do not have exposed bone. MRI is the imagingof choice for the evaluation of foot osteomyelitis; plain foot radiography is highly spe-cific but has a very low sensitivity.63,64 Definitive diagnosis is based on histopathologyand culture of a bone biopsy.

Surgical resection of necrotic tissue or bone is necessary to achieve cure and im-prove outcome.56,65,66 In patients with poor oxygen tension, revascularization shouldbe done e if possible prior to any surgical debridement. Aggressive revascularizationto maintain adequate arterial perfusion is a critical factor in maintaining limb sal-vage.56,67 When possible, parenteral antimicrobial therapy, usually given for 4e6 weeks,should be based on culture results. Shorter treatment courses are possible when theaffected bone has been resected.66,68 Whether patients with minimal cortical osteomy-elitis diagnosed on imaging studies can be treated with prolonged antimicrobial therapywithout surgical debridement is subject to great debate.69

SAPHO syndrome

The syndrome of synovitis, acne, plantar pustulosis, hyperostosis and osteitis (SAPHO)is a clinical entity of unknown cause characterized by hyperostosis, commonly involvingthe bones of the anterior chest wall, and a chronic or relapsing skin eruption.70 Patients

Table 6. Factors associated with an increased risk of foot ulcers in patients with diabetes mellitus.

� Diabetes mellitus duration of more than 10 years

� Poor glucose control

� Cardiovascular disease

� Renal or retinal complications

� Peripheral neuropathy

� Evidence of increase local pressure, e.g. callus, erythema

� Limited joint mobility

� Peripheral vascular disease

� A prior history of foot ulcer

� A prior history of amputation

Osteomyelitis 1075

typically present with musculoskeletal complaints, and local swelling and tenderness ofaffected bones are often present. Osteitis is typically multifocal and affects severalbones, including the chest-wall bones, pelvis, and spine. Many patients have sometype of pustular dermatosis. Systemic symptoms of fever, weight loss, and generalizedmalaise are rare. The disease is self-limited, with intermittent periods of exacerbationand remission. Diagnosis can be difficult, and lesions can be confused with infectiousosteomyelitis. Mean interval between symptom onset to diagnosis can be up to 9years.71 Diagnosis is based on the exclusion of infectious arthritis or osteomyelitis.The differential diagnosis includes infectious osteomyelitis, Paget’s disease, tumor,and other inflammatory arthritides.

There are no specific laboratory tests to diagnose SAPHO. Radiologic findings in-clude osteolysis, osteitis, hyperostosis, and osteosclerosis. Bone biopsy and culturesare required for diagnosis in order to exclude infectious osteomyelitis. Histopathologyis typically non-specific, with a combination of acute and chronic inflammatory cells.Cultures of biopsy material are negative for bacteria (including mycobacteria) andfungi.72 Non-steroidal anti-inflammatory drugs (NSAIDs) and intra-articular injectionsare often prescribed; methotrexate and prednisone are sometimes necessary.71 Othertherapeutic modalities such as pamidronate and infliximab have been used with somesuccess in small numbers of patients.73,74 When used, antimicrobials appear to have noimpact on the course of this illness.

Another closely related syndrome is chronic recurrent multifocal osteitis(CRMO).75 This syndrome mainly affects children and adolescents, and typically affectsbones of the lower extremities.

Osteomyelitis in patients with rheumatoid arthritis

Patients with rheumatoid arthritis are at increased risk of infections.76,77 The use ofimmunomodulating and immunosuppressive agents such as steroid, methotrexate, tu-mor necrosis factor-a inhibitors, and interleukin-1 inhibitors can increase the risk fora variety of bacterial (including mycobacterial) and fungal infections. Furthermore,a higher colonization rate with S. aureus and the immunologic changes related tothe disease itself can increase the risk for infections. Recently, a large longitudinal ret-rospective cohort study compared 609 patients with rheumatoid arthritis to thosewithout rheumatoid arthritis. The rate ratio for the presence of osteomyelitis in pa-tients with rheumatoid arthritis was 10.6, with 95% confidence intervals of3.39e126.81.76 There is a higher incidence of S. aureus, mycobacterial and fungal in-fections in patients with rheumatoid arthritis.78 Although septic arthritis is more com-mon than osteomyelitis patients can frequently present with bacteremia and multifocalhematogenous infection involving multiple joints, spine, and long bones osteomyelitis.The signs and symptoms of osteomyelitis in patients with rheumatoid arthritis oftenmasquerade as an exacerbation of the rheumatoid arthritis. The treating clinicianwill need to have a high index of suspicion and include osteomyelitis in the differential.The management of osteomyelitis in patients with rheumatoid arthritis is often com-plicated by a high relapse rate. This is likely due to the underlying comorbidities andthe immunosuppressed state of patients. The discontinuation of all immunomodulat-ing agents as soon as the diagnosis of osteomyelitis is made, and delaying the reinsti-tution of these drugs for at least 6 months after the resolution of the signs andsymptoms of infection, is often recommended.78


Culture-negative osteomyelitis

Culture-negative osteomyelitis is a poorly defined entity. Most often it indicates thepresence of purulence, acute histopathologic changes, and suggestive clinical andradiological findings of osteomyelitis coupled with negative microbial cultures. It isthe experience of the authors that most of these cases are related to prior useof antimicrobials. A small percentage of these cases can be due to the presenceof fastidious microorganisms or microorganisms that require specialized culture me-dia. Furthermore, some of these cases can be related to a non-infectious illness: e.g.SAPHO syndrome, avascular necrosis, radiation changes, sickle cell disease, and neu-ropathic changes. Children with culture-negative osteomyelitis are less likely to haveantecedent trauma and overlying skin changes when compared to culture-positivecases.79 Additionally, the duration of symptoms tends to be longer in culture-negative cases. When bacterial/anaerobic cultures fail to grow any microorganismafter a few days of incubation, fungal and mycobacterial cultures of bone specimensare often done as well. In patients with immunoglobulin deficiency, mycoplasma cul-tures should also be done. Bone tissue can also be sent for broad-range polymerasechain reaction (PCR) analysis with the use of 16S rRNA gene primers. Theseprimers have broad specificity in detecting bacterial DNA and can occasionallyhelp with the diagnosis of culture-negative osteomyelitis.80,81 Therapy of culture-negative skull-base osteomyelitis with systemic antipseudomonal antimicrobials for6 weeks has recently been reported to result in a high cure rate.82 The treatmentof culture-negative osteomyelitis often follows the same principles as culture-positivecases. The choice of antimicrobials is empiric, and based on the patient’s history andthe type of osteomyelitis.

Other forms of osteomyelitis

Septic arthritis of the pubic symphysis is a rare condition and should be differenti-ated from osteitis pubis, a non-infectious inflammation of the joint often seen in ath-letes. It is an infection of the symphysis pubis recognized as a complication of variousgynecologic and urologic surgeries, including MarshalleMarchettieKrantz urethro-pexy, prolonged catheterization, inguinal hernia repair, and vaginal delivery.83e85

S. aureus, Enterococcus sp, Escherichia coli, Pseudomonas sp, and Proteus sp are themost common causative microorganisms. Most patients present with suprapubicpain and difficulty with ambulation. The time between surgery and diagnosis canrange from 2 to 18 months.84 Fever and leukocytosis are rarely present; an elevatedsedimentation rate is present in two thirds of patients.85 Plain radiograph may benormal early on; radiographs performed 6 months later can reveal pubic bone scle-rosis, joint space widening, and rarefaction. CT scan and MRI are more sensitive indetecting bony changes than plain radiography, and can define the soft tissue muchbetter. Bone or 111In -labeled white blood cell scan is very sensitive. Fine-needle as-pirate is sometimes helpful. Osteitis pubis could be managed with NSAIDs and cor-ticosteroids; antimicrobial therapy should be administered in osteomyelitis of thepubic bone. Surgical debridement of infected bone may be required in more than70% of cases.85

Osteomyelitis of the clavicle represents less than 3% of osteomyelitis cases.86e88 Itmay be from a hematogenous source or related to subclavian vein catheterization andneck surgery. S. aureus is the single most common microorganism implicated. A variety

Osteomyelitis 1077

of other microorganisms e including gram-negative bacteria and M. tuberculosis e havebeen described. All patients typically present with clavicular site pain, either as acutelocal pain and swelling with positive blood cultures (e.g. S. aureus) or more chronic andindolent in nature (e.g. M. tuberculosis). Fever, localized swelling or mass, and soft-tissue abscesses are present in 60%, 30%, and 30% of cases, respectively; durationof symptoms can range from 2 weeks to 18 months.86 Plain radiographs of the claviclemay show sclerotic or lytic changes. Given its non-traumatic nature, most cases of cla-vicular osteomyelitis present a therapeutic challenge. Acute cases can be treated withparenteral antimicrobial therapy alone (Table 4). Chronic cases should be managedwith surgical debridement and antimicrobial therapy.

Sacroiliac joint infection is an uncommon metastatic infection of S. aureus bacter-emia.89 Intravenous drug abusers and patients with indwelling vascular catheters areat risk. Patients typically present with acute onset of sacral and/or pelvic pain and leu-cocytosis. Blood cultures are often positive. Patients should be evaluated for the pres-ence of concomitant infective endocarditis.

FOLLOW-UP OF PATIENTS WITH OSTEOMYELITIS

The optimal follow-up of patients with osteomyelitis is the subject of great debate. Atthe author’s institution, the follow-up depends largely on the type of osteomyelitis. Inpatients with surgical wounds and flaps, the follow-up depends on the healing status ofthe incision and the viability of the flap. Persistence of wound drainage and the devel-opment of sinus tract are often associated with the persistence of the underlying os-teomyelitic process. In patients with traumatic and surgical fractures, the presence ofbony fusion on follow-up imaging studies is often associated with the lack of active os-teomyelitis. The use of systemic inflammatory markers such as ESR and CRP can beuseful in selected patients. In our opinion, a persistently elevated CRP but not ESRat 4e6 weeks can be associated with persistent osteomyelitis. The persistence ofsoft-tissue abnormalities at 6 weeks on follow-up MRI in patients with native spine in-fection is a bad prognostic sign.50 The use of nuclear imaging in the follow-up of pa-tients with osteomyelitis is not useful as it can normally take up to 12 months for itto normalize.

Patients receiving prolonged antimicrobial therapy should have a weekly completeblood cell count, and liver and kidney function tests should be performed to monitorfor any adverse reaction.

CONCLUSION

Despite important medical and surgical advances in the management of patients withosteomyelitis, this disease remains extremely difficult to treat. The relapse rate can beas high as 20%. The optimal management of osteomyelitis requires a multidisciplinaryteam of physicians that might include an orthopedic surgeon, a neurosurgeon, an oralsurgeon, a plastic surgeon, a rheumatologist, a vascular surgeon, an invasive radiologist,and an infectious disease specialist. The usual goal of therapy is the eradication of theinfection and restoration of function. Treatment of established osteomyelitis requiresaggressive surgical debridement and prolonged antimicrobial therapy in the majority ofcases.


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Practice points

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osteomyelitis

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