Osteomyelitis

UpDated Feb 2018

• Osteomyelitis is one of the oldest recorded diseases, with descriptions
dating back to the time of Hippocrates (460 to 370 BC) [1]. Terms such
as "abscessus in medulla," "necrosis," and "a boil of the bone
marrow" were used to describe the infection until Nélaton introduced
the term "osteomyelitis" in 1844.
• PATHOPHYSIOLOGY — 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.
• Hematogenous osteomyelitis is usually monomicrobial,
• while osteomyelitis due to contiguous spread or direct inoculation is
usually polymicrobial.
• In long-bone hematogenous osteomyelitis, the most common site of
infection is in the metaphysis.
• The major blood vessel to long bones usually penetrates the midshaft
of the bone and then travels toward both ends, forming metaphyseal
vascular loops just before it hits the epiphyseal plates.
• Slowed blood flow in these loops (together with the absence of
basement membranes) predisposes this site to osteomyelitis.
• In the setting of osteomyelitis, inflammatory exudate in the marrow
leads to increased intramedullary pressure, with subsequent
extension of exudate into the bone cortex where it can rupture
through the periosteum. If this occurs, the periosteal blood supply is
interrupted, leading to necrosis. The resulting pieces of separated
dead bone (known as sequestra) can be visualized radiographically.
New bone formation that forms in areas of periosteal damage is
known as an involucrum. In some cases, a sequestrum can evolve into
an involucrum as it is encased with new bone growth. Occasionally,
pus may exist in an opening (cloaca) of involucrum
• Acute osteomyelitis is infection in bone prior to development of
sequestra. In some forms of infection, 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 chronic osteomyelitis; other hallmarks of chronic
osteomyelitis include formation of an involucrum, local bone loss, and
sinus tracts (if there is extension of infection through cortical bone).
• In the setting of vertebral osteomyelitis, two endplates of neighboring
vertebra are frequently involved in the infection. This observation can
be explained by the blood supply anatomy; one arterial vessel splits to
supply the neighboring endplates of two vertebra.
CLASSIFICATION 
• Lew and Waldvogel classified osteomyelitis based on the duration of
illness (acute versus chronic) and the mechanism of infection
(hematogenous or secondary to a contiguous focus of infection).
Contiguous infection may be further subdivided depending upon
whether vascular insufficiency is present. This scheme is an etiologic
classification and does not imply a specific therapeutic strategy
• Cierny and Mader classified long-bone osteomyelitis based on the
affected portion of the bone, the physiologic status of the host, and
the local environment (table 1) [5]. This classification lends itself to
the treatment and prognosis of osteomyelitis; stage 1 (medullary
osteomyelitis) can usually be treated with antibiotics alone, while
stages 2, 3, and 4 (superficial, localized, and diffuse osteomyelitis)
usually require aggressive debridement, antimicrobial therapy, and
subsequent orthopedic reconstruction
• MICROBIOLOGY — Hematogenous osteomyelitis is usually
monomicrobial, while contiguous osteomyelitis may be either
polymicrobial or monomicrobial. Staphylococcus aureus, coagulase-
negative staphylococci, and aerobic gram-negative bacilli are the most
common organisms; other pathogens including streptococci,
enterococci, anaerobes, fungi, and mycobacteria have also been
implicated
• EPIDEMIOLOGY — Hematogenous osteomyelitis occurs more
commonly in children than adults; in children, long bones are most
often affected, while in adults the vertebrae are the most common
site [9].
• Contiguous osteomyelitis tends to occur in younger individuals in the
setting of trauma and related surgery, and, in older adults, secondary
to decubitus ulcers and infected total joint arthroplasties [4].
• Osteomyelitis associated with vascular insufficiency usually occurs
among individuals with diabetes mellitus.
• CLINICAL MANIFESTATIONS — Osteomyelitis can occur as a result of
contiguous spread of infection to bone from adjacent soft tissues and
joints, hematogenous seeding, or direct inoculation of infection into
the bone as a result of trauma or surgery.
• Overview — 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. However, patients with
osteomyelitis involving sites such as the hip, vertebrae, or pelvis tend
to manifest few signs or symptoms other than pain. Subacute
osteomyelitis generally presents with mild pain over several weeks,
with minimal fever and few constitutional symptoms
• Acute osteomyelitis can also present as septic arthritis. As noted above, in
long-bone hematogenous osteomyelitis, the most common site of infection is
in the metaphysis. If infection spreading from the metaphysis breaks through
the bone cortex within the capsular reflection of a joint, discharge of pus into
the joint presents as a septic arthritis secondary to osteomyelitis. Joints in
which the long-bone metaphysis is within the joint capsular reflection
include the knee, hip, and shoulder. This is particularly important in infants,
for whom the presence of transphyseal blood vessels and an immature
growth plate allows early spread of bacteria from the metaphysis to the
epiphysis of the bone and into the joint cavity. In these cases, infection that
begins in the bone can spread into the joint quickly, leading to septic
arthritis.
• Chronic osteomyelitis may present with pain, erythema, or swelling,
sometimes in association with a draining sinus tract. The presence of
a sinus tract is pathognomic 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 present [10]. 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 [10,11]. Additional
presentations of chronic osteomyelitis include nonhealing fractures
and Brodie's abscess
• Diabetic patients with chronic osteomyelitis may present with atypical
physical findings. Diabetics who develop cutaneous ulcers often
develop osteomyelitis before exposed bone is present on exam [10]. If
a diabetic foot ulcer is larger than 2 x 2 cm or if exposed bone is
present, osteomyelitis is highly likely
• Probing to bone — Probing for bone with a sterile blunt metal tool should be
included in the initial assessment of all diabetic patients with infected pedal
ulcers. A positive result consists of detection of a hard, gritty surface [11-13].
The reliability of the probe-to-bone test may vary by the ulcer location and
the expertise of the clinician performing the test [14,15]. The probe-to-bone
test should be used as a screening tool in conjunction with the patient's pre-
test probability for osteomyelitis to determine whether additional diagnostic
tests (such as radiographic imaging or bone biopsy) are needed for
therapeutic decisions. The performance characteristics of the probe-to-bone
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.
• 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 0.87
(95% CI 0.65-0.93) and 0.83 (95% CI 0.65-0.93), respectively [16]. An
important limitation was the potential for selection and verification
bias; the studies included in the analysis did not explicitly mention
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 may be used in a high-prevalence settings
(such as the emergency department or inpatient hospital ward) as a
screening test or in a low-risk setting (such as outpatient primary care
clinic) to rule out diabetic foot osteomyelitis. As the prevalence of
diabetic foot osteomyelitis increases, the sensitivity of the test
increases and the specificity of the test decreases [
• Laboratory tests — Laboratory tests are usually nonspecific.
Leukocytosis may be observed in the setting of acute osteomyelitis but
is unlikely in the setting of chronic osteomyelitis. The erythrocyte
sedimentation rate and/or C-reactive protein are usually elevated but
may be normal [17,18]. Blood cultures may be positive in about half of
cases of acute osteomyelitis; their utility may be highest in the setting of
hematogenous infection [4]. Blood cultures are also more likely to be
positive in vertebral disease and when hematogenous osteomyelitis
involves locations such at the clavicle or pubis [19,20]. Positive blood
cultures may obviate the need for invasive diagnostic testing if the
organism isolated from blood is a pathogen likely to cause osteomyelitis.
• DIAGNOSIS — Acute osteomyelitis should be suspected in bacteremic
patients at risk of seeding vertebrae, long bones, and bone and joint
prostheses in cases of open fractures or recent surgery. Chronic
osteomyelitis should be suspected in patients with chronic, poorly
healing soft tissue wounds, in the setting of diabetes, peripheral
neuropathy, decubitus ulcers, or in the presence of underlying
hardware
• The diagnosis of osteomyelitis is established via culture of bacteria from
a bone biopsy obtained via sterile technique, together with histologic
findings of inflammation and osteonecrosis [11]. Bone biopsy may not
be needed for patients with radiographic studies consistent with
osteomyelitis in the setting of positive blood cultures. Laboratory
findings are nonspecific and may include leukocytosis and elevated
serum inflammatory markers (erythrocyte sedimentation rate
[ESR] and/or C-reactive protein [CRP])
• Establishing an accurate diagnosis of osteomyelitis is critical, since the
infection can require prolonged antibiotic therapy and/or aggressive
surgical intervention.
• 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, injection drug use, and other
predisposing factors). The probe-to-bone test should be used as a
screening tool in conjunction with the patient's pre-test probability
for osteomyelitis to determine whether additional diagnostic tests
(such as radiographic imaging or bone biopsy) are needed for
therapeutic decisions.
• If osteomyelitis is suspected based on clinical history and physical
findings, plain radiographs of the involved area should be obtained
along with laboratory evaluation (including ESR, CRP, white blood cell
count, and blood cultures; the yield of blood cultures is likely highest
in the setting of associated fever and/or in the setting of suspected
vertebral osteomyelitis).
• If plain radiographs are normal or have findings suggestive of
osteomyelitis without characteristic features, a more sophisticated
imaging modality should be pursued in the clinical setting of risk
factors (such as diabetes, localized symptoms, and/or an elevated
ESR). The optimal 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
• If the patient is diabetic and has symptoms referable to the foot,
magnetic resonance imaging (MRI) is the test of choice.
• ●If the patient has symptoms referable to the spine, MRI is the test of
choice to evaluate for vertebral osteomyelitis. If MRI is not available,
computed tomography (CT) is the alternative test of choice.
• ●If metal hardware precludes MRI or 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 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). 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 (table 2).
• 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
• 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 [22-26].
Cultures of bone biopsy material yield positive findings in up to 87 percent of
cases [23]. Cultures of swabs or material from needle puncture (eg,
aspiration of material adjacent to the periosteum rather than bone) should
not be used to establish an osteomyelitis pathogen, since the correlation
between bone biopsy culture and these specimens is poor [26,27]. 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 [28
].
• Percutaneous needle biopsy is an alternative to open biopsy, although 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 [27]. In addition, the sensitivity of needle biopsy can be
particularly low in postoperative or posttraumatic settings [23,29]. 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
computed tomography 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 radiolographic 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.
• 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
for histopathology [30].
• Cultures of superficial wounds and sinus tracts are of no value because
the results do not correlate reliably with the pathogen in the underlying
bone [26,29,31]. Although sinus tract cultures may be of some use for
prediction of osteomyelitis if S. aureus or Salmonella spp are identified,
in general, such cultures are not worthwhile [32,33].
• 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 [31]. 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 [
31].
• Sonication of explanted hardware may be useful to detect
microorganisms that are highly adherent to fixation hardware, although
this procedure is not routinely available in most microbiology
laboratories [
• Histopathology — Histopathologic features of osteomyelitis include
necrotic bone with extensive resorption adjacent to an inflammatory
exudate [36]. Stains for bacteria, mycobacteria, and fungi should be
on histopathology specimens.
• 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 in detail separately
• DIFFERENTIAL DIAGNOSIS — The differential diagnosis of
osteomyelitis includes:
• ●Soft tissue infection – Soft tissue infection may occur alone or in
conjunction with osteomyelitis. Probing to bone is sufficient for
diagnosis of 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
• 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. Bone scans, plain radiographs,
and magnetic resonance imaging (MRI) findings in patients with acute or
chronic neuroarthropathy may be indistinguishable from patients with acute
osteomyelitis. However, contrast-enhanced MRI 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 in the
preceding situations and in cases of presumed acute Charcot arthropathy in
which rest, immobilization, and elevation do not result in improvemen
• Osteonecrosis – Osteonecrosis (avascular necrosis of bone) is usually
relatively easy to distinguish from osteomyelitis as a precipitating
cause such as steroid, radiation, or bisphosphonate use is present.
Associated osteomyelitis may occur in patients with mandibular
osteonecrosis.
• Gout – Both osteomyelitis and gout can present with joint
inflammation. Gout is distinguished by presence of uric acid crystals in
joint fluid; the presentation is relatively acute, while the presentation
of osteomyelitis is relatively chronic
• 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.
• 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
• Malignancy – Both osteomyelitis and malignancy may present with
bone pain; malignancy is generally distinguished by radiographic
imaging and bone biopsy
• 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.
TREATMENT
• Debridement — Osteomyelitis frequently requires both surgical
therapy for debridement of necrotic material together with
antimicrobial therapy for eradication of infection. In certain
circumstances, surgical treatment may also require hardware
placement or removal and/or revascularization.
• Antibiotic selection — Whenever possible, antibiotic therapy should
be delayed in stable patients until tissue cultures can be obtained.
• Antibiotic therapy should be tailored to culture and susceptibility
findings. If culture results are not obtainable, broad-spectrum empiric
therapy should be administered. Suggested antibiotic regimens and
bone penetration data are outlined in the tables (table 2 and table 3) [
37-42].
• Issues related to treatment of prosthetic joint infections are discussed
separately.
• Infection due to S. aureus — Empiric treatment of osteomyelitis due to S. aureus should consist of
antimicrobial therapy with activity against methicillin-resistant S. aureus (MRSA) until further
microbiology data become available. Subsequent treatment should be guided by susceptibility data.
• MSSA — Treatment of osteomyelitis due to methicillin-susceptible S. aureus (MSSA) usually consists of
parenteral therapy.
• Use of adjunctive agents for treatment of S. aureus osteomyelitis may be warranted in some
circumstances. (See 'Use of adjunctive agents' below.)
• For patients who are not candidates for outpatient parenteral antibiotic therapy, treatment of
osteomyelitis due to MSSA with oral agents may be an acceptable alternative approach [43-45]. In one
study of 50 patients with chronic osteomyelitis treated with antibiotics following debridement, oral
therapy with rifampin and trimethoprim-sulfamethoxazole demonstrated comparable efficacy to
intravenous cloxacillin therapy [43]. In another study including 20 patients with osteomyelitis,
prolonged oral therapy with rifampin-cotrimoxazole or rifampin-linezolid was equally effective; cure
rates were 78 and 89 percent, respectively [44]. These trials had very small sample sizes, limiting
detection of significant differences between the treatment groups.
• MRSA — Initial treatment of osteomyelitis due to methicillin-resistant S.
aureus consists of parenteral therapy. The antibiotic of choice for treatment of
MRSA osteomyelitis is vancomycin (table 4); it is the antibiotic agent for which
there is the greatest cumulative clinical experience for treatment of bacteremia
caused by MRSA [46,47].
• Daptomycin (and teicoplanin, where available) are acceptable alternative agents to
vancomycin [48-52]. Daptomycin was proposed as an alternative to standard
therapy for treatment of patients with S. aureus osteoarticular infections based on
a post hoc analysis of a randomized trial comparing daptomycin with vancomycin or
anti-staphylococcal penicillin with initial gentamicin for treatment of 121 patients
with S. aureusbacteremia [48]. Osteoarticular infection occurred in 32 patients (21
who received daptomycin and 11 who received standard therapy).
• Potential agents for treatment of osteomyelitis that warrant further
study include ceftaroline and telavancin [53,54]. Use of linezolid and
tedizolid are limited by toxicity and cost; these should be reserved for
patients who do not respond to or cannot tolerate other agents [
55-57]. Additional issues related to agents with activity against MRSA
are discussed further separately. (See
"Methicillin-resistant Staphylococcus aureus (MRSA) in adults: Treatme
nt of bacteremia", section on 'Drugs with activity against MRSA'
.)
• Use of adjunctive agents for treatment of S. aureus osteomyelitis may
be warranted in some circumstances
• In the setting of insufficient debridement or persistently elevated inflammatory markers
after completing a course of parenteral therapy (typically 6 to 8 weeks), some favor
treatment with oral consolidative therapy [45,58]. Possible regimens include
trimethoprim-sulfamethoxazole (4 mg/kg of the trimethoprim component twice daily)
with rifampin (600 mg once daily), linezolid (600 mg orally or intravenously [IV] twice
daily), or clindamycin(600 mg orally or IV three times daily) [43,46,55,59-61]. Data for
trimethoprim-sulfamethoxazole plus rifampin is extrapolated from experience with
MSSA, as discussed above [43]. (See 'MSSA' above.)
• Data regarding the efficacy of tetracyclines for consolidative therapy are limited; use of
this class may be reasonable for chronic suppression of retained infected hardware
following definitive treatment of osteomyelitis. (See 'MSSA' above.)
• There is no role for use of quinupristin-dalfopristin, tigecycline, or fluoroquinolones for
treatment of MRSA osteomyelitis.
• Use of adjunctive agents — Some favor adjunctive 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); others oppose its use given
limited evidence for improved outcomes over standard antimicrobial
therapy [46,62,63].
• 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 to oral agents. Use of rifampin
must be weighed against the likelihood of toxicity and drug interactions
• Rifampin must be combined with another active antibacterial agent
because rapid emergence of resistance in the setting of rifampin
monotherapy is common. Rifampin (600 mg daily [single dose or in two
divided doses] to 900 mg daily [in two or three divided doses]) should
be initiated only once infection is under good control; resistance is less
likely to emerge when fewer organisms are present [63,65]. (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; it has
been used successfully with rifampin and flucloxacillin
• Infection due to gram-negative organisms — For treatment of
osteomyelitis due to gram-negative organisms, fluoroquinolones are
excellent agents (if susceptibility testing confirms their sensitivity to
these agent) since they have high bone penetration with oral
administration
• Duration of therapy — Antibiotic therapy of osteomyelitis requires a prolonged duration of
treatment, typically in the form of outpatient parenteral antibiotic therapy. This may be in part
due to the observation in experimental models that S. aureus can persist following digestion by
osteoblasts [3,68]. In addition, antibiotic penetration into bone may be unreliable in some
patients, particularly in those with vasculopathy or prior extensive scarring from trauma.
• The optimal duration of antibiotic therapy is not certain; most experts favor continuing
parenteral 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 [69]. Antimicrobial
therapy may be administered on an outpatient basis via a long-term intravenous catheter with
close monitoring (depending on the antibiotic agent, monitoring may include weekly serum
drug levels, renal function, liver function, and/or hematologic function).
• Serial weekly measurements of serum inflammatory markers (erythrocyte sedimentation
rate and/or C-reactive protein) can be useful. If these test results have not normalized by the
end of the planned treatment course, further clinical and/or radiographic investigation may
be pursued [70].
• If orthopedic hardware that is known or presumed to be infected must be retained
indefinitely, long-term antibiotic suppression with an oral agent may be warranted. Such
long-term oral therapy is usually preceded by parenteral therapy until clinical signs of acute
infection have resolved. The optimal duration of oral antibiotic suppression is uncertain.
Three to six months may be reasonable; continuing suppressive treatment for longer than six
months may not be as beneficial [71].
• If the osteomyelitic bone has been fully resected (as when amputation is performed), a
much shorter course of antibiotic therapy may be sufficient. In such cases, antibiotic therapy
can usually be discontinued when operative wounds are healing without signs of infection.
• Adjunctive therapies — Adjunctive therapies for osteomyelitis include
hyperbaric oxygen (HBO) and negative pressure wound therapy
(NPWT), also called vacuum-assisted closure. Osteomyelitis is often
associated with reduced intra-osseus blood flow and consequent
reduced oxygen tension in infected bony tissue. This in turn may limit
neutrophil and macrophage activity [72-75]. As a result, hyperbaric
oxygen may be a useful adjunctive therapy in a small percentage of
patients with refractory osteomyelitis. In one series including 142
patients with refractory osteomyelitis treated with HBO, successful
healing without relapse was observed in 73 percent of patients
• COMPLICATIONS — In the absence of appropriate therapy, acute
osteomyelitis can be associated with disabling or life-threatening
complications. Suppurative infection may involve contiguous
structures such as the joints and soft tissues, leading to sinus tract
formation. Osteolysis and pathologic fractures have been described,
although such complications are exceedingly rare with early
recognition and treatment [76]. Infrequently, hematogenous spread
and sepsis can occur, although it may be difficult to determine
whether the primary source of infection is the bloodstream or bone.
• Sinus tract formation may be associated with neoplasms, especially in the
setting of longstanding infection (range 4 to 50 years) [77]. Squamous cell
carcinoma is the most common tumor associated with chronic osteomyelitis;
other tumors have been reported including fibrosarcoma, myeloma,
lymphoma, plasmacytoma, angiosarcoma, rhabdomyosarcoma, and
malignant fibrous histiocytoma [77-84]. Most patients with neoplasm have a
history of repeated surgical interventions. Development of a malignant
tumor is heralded by an enlarging mass, increasing pain, foul-smelling
drainage, bleeding, or radiographic evidence of bone destruction. Therefore,
recalcitrant infection that does not respond to conventional therapy should
prompt biopsy evaluation for malignancy from multiple sites (including the
ulcer, sinus tract, and underlying bone).
Pathogenesis of osteomyelitis
• INTRODUCTION — Osteomyelitis is a progressive infection of bone
that results in inflammatory destruction followed by new bone
formation. Three major categories are based upon pathogenic
mechanisms of infection [1]:
• ●Osteomyelitis secondary to a contiguous focus of infection (eg, after
trauma, surgery, or insertion of a prosthetic joint).
• ●Osteomyelitis secondary to a contiguous focus of infection
associated with vascular insufficiency, primarily occurring in patients
with diabetes mellitus and/or peripheral vascular disease
• Osteomyelitis following hematogenous spread of infection, which is
the major mechanism in vertebral osteomyelitis and in children. It was
previously thought that spread of infection may occur via vertebral
veins known as Batson's plexus, especially from sites of infection in
bowel or urinary tract. Seeding beneath the vertebral endplate is
followed by involvement of the disc and other adjoining vertebrae.
Blood vessels in pediatric spine terminate within the intervertebral
disc, allowing for direct extension of infection [2]. Many experts now
believe that the corkscrewing of the vertebral arterial supply leads to
vertebral osteomyelitis in patients with bacteremia.
• 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.
• PATHOGENESIS — Normal bone is highly resistant to infection. Thus, osteomyelitis
arises only when there is a large organism inoculation, trauma leading to bone
damage, or the presence of foreign material. 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.
• Bacteria have a variety of virulence determinants that can contribute to the
development of osteomyelitis in the appropriate clinical setting. Staphylococcus
aureus, the most common cause of osteomyelitis, has been extensively used as a
model to study pathogenesis. It is an important cause of both hematogenous and
contiguous focus osteomyelitis and produces a number of 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. aureusadheres to a number of components of
bone matrix including fibrinogen, fibronectin, laminin, collagen, bone sialoglycoprotein, and
clumping factor A [3-7]. Adherence is mediated by expression of specific adhesins, called
microbial surface components recognizing adhesive matrix molecules (MSCRAMM) [3,8].
• 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 percent versus 27 percent) [9]. The adhesin-positive strains were also
associated with the production of high levels of immunoglobulin G and interleukin 6. In
other experimental studies, S. aureus adhesion was blocked by antibodies directed against
the collagen receptor [10]. It has been speculated that bone and other invasive S.
aureus infections might be prevented by an adhesin-derived vaccine
• Collagen-binding adhesin (CNA) of S. aureus is a virulence factor for
arthritis in several animal models [12,13]. The expression of CNA
permits the attachment of pathogen to cartilage [14]. 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 [5].
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
• Proteolytic activity — Potential proteolytic activity present in normal
joints is inhibited in the absence of infection. However, this protective
effect may be lost with infection. In an in vitro model of adult
chondrocytes inoculated with S. aureus, for example, overall protein
synthesis was reduced by 84 percent, with an increase in the release
of collagenase and gelatinase
• Resistance to host defense — The ability of microorganisms to resist
host defense mechanisms at both the cellular and matrix levels presents
difficulties in the treatment of osteomyelitis.
• 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 [17,18]. Osteoblast persistence of S. aureus in chronic
osteomyelitis has been described
• 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 — 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
• 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 osteomyelitis, even though extensive, is usually
absorbed. Some of the dead cortical bone is gradually detached from living bone to form a
sequestrum [27,28].
• 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
• 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 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 [31]. 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 [32,33]. 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 staphylococcal osteomyelitis [34]. 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
• 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)
Hematogenous osteomyelitis in
adults
• INTRODUCTION — Hematogenous osteomyelitis accounts for
approximately 20 percent of cases of osteomyelitis in adults. It occurs
more frequently in males. Hematogenous osteomyelitis most
commonly involves the vertebral bones; the next most common sites
are the flat bones of the axial skeleton, such as the clavicle and pelvis.
Less frequently, the long bones of the appendicular skeleton can be
involved
• EPIDEMIOLOGY — Hematogenous osteomyelitis is primarily a disease of
children, with 85 percent of cases occurring in patients younger than 17
years of age [2]. The proportion of adult cases may be increasing as the
mean age of the population rises in the United States and developed
countries [3].
• Most cases in adults are observed in patients over age 50, with the
exception of intravenous drug users (the majority of whom are under age
40) [4]. Hematogenous osteomyelitis is also associated with intravascular
devices including vascular catheters and cardiovascular devices [5] and
other risk factors for bacteremia (eg, dialysis, sickle cell disease, urethral
catheterization, urinary tract infection, intravenous drug abuse)
• The site of infection varies with age. In children, the most common sites of involvement are the
long bones (eg, femur, tibia, and humerus); vertebral osteomyelitis accounts for only 1 to 2 percent
of cases [6]. In adults, the long bones are rarely involved; the major sites of infection are the
vertebrae and the sternoclavicular and pelvic bones (the last two most commonly occurring in
intravenous drug users) [7]. (See
"Pelvic osteomyelitis and other infections of the bony pelvis in adults".)
• Among adult patients with hematogenous infection of the hip, magnetic resonance imaging has
demonstrated that infection commonly extends distal to the femoral head into the medullary canal
of the femur or acetabulum [8].
• Among patients with vertebral osteomyelitis, the lumbar vertebral bodies are most often involved,
followed in frequency by the thoracic and cervical vertebrae. Spread to adjacent vertebral bodies
may occur rapidly through the rich venous networks in the spine. Posterior extension may lead to
epidural and subdural abscesses or even meningitis. Extension anteriorly or laterally can lead to
paravertebral, retropharyngeal, mediastinal, subphrenic, retroperitoneal, or psoas abscesses
• PATHOGENESIS — The development of hematogenous osteomyelitis
depends upon a clinical triad including presence of local or systemic
immunocompromise, the number of organisms present and their
virulence properties.
• Host factors — The mechanism of infection in hematogenous
osteomyelitis in children is thought to be due to specific features of
long bone anatomy
• In the setting of long bone hematogenous osteomyelitis in adults, infection usually begins in the
diaphysis but may spread to involve the entire medullary canal. Extension into the epiphysis and joint
space can occur, since the growth plate has matured and shares vessels with the metaphysis. Since the
periosteum is firmly adherent to the bone, cortical penetration usually leads to a soft tissue abscess.
Subperiosteal abscesses and massive cortical devitalization occur rarely. Sinus tracts connecting the
sequestered nidus of infection to the skin can develop over time [10].
• The mechanism of bacterial deposition in the metaphysis is unclear. Examination of the capillary loops
of the metaphyseal vessels by electron microscopy has shown that the distal vessels are composed of
a single layer of discontinuous endothelium through which tracer particles can escape [11,12]. It is
possible that bacteria also pass through these gaps during an episode of bacteremia, thereby initiating
osteomyelitis [13]. In addition, the metaphyseal capillaries lack phagocytic lining cells, and the
sinusoidal veins contain functionally inactive phagocytic cells, both of which allow growth of
microorganisms [14].
• Any form of end-capillary obstruction, including intraosseous bleeding or subperiosteal hematoma as
the result of minor trauma, can produce an area of avascular necrosis that is predisposed to infection.
• Bacterial factors — The pathogenesis of hematogenous osteomyelitis depends on the
ability of specific bacteria to bind to host tissue and avoid clearance by the host
immune response. Most cases of hematogenous osteomyelitis are due
to Staphylococcus aureus. Other bacterial species include Streptococcus
pyogenes (group A Streptococcus) and other Streptococcus species and more
rarely Kingella kingae, Enterococcus species, and other coagulase-negative
staphylococci including Staphylococcus lugdunensis, Staphylococcus
epidermidis, and Staphylococcus simulans.
• S. aureus is by far the most commonly isolate; it has an array of virulence mechanisms
to avoid the host immune response, more than 20 different toxins, and a plethora of
adhesins known as "microbial surface components recognizing adhesive matrix
molecules" (MSCRAMMs). These adhesins can adhere to tissue by binding host
proteins including fibronectin, fibrinogen, and collagen
• Once bound, S. aureus organisms multiply, down-regulate adhesion
production, up-regulate toxin secretion, and promote an ineffectual
inflammatory host response that produces collateral host tissue
damage. If inadequately treated with effective antibiotics and surgical
intervention, S. aureus can form a mature biofilm. Once in this mature
microbial community, bacteria are 100 to 1000 times more tolerant to
antimicrobial agents than the free-floating planktonic bacteria seen
during the acute phase of the disease [16]. The result is a disease
where source control involves surgical removal of the infectious nidus
and culture-directed antibiotics in order to resolve the infection
• MICROBIOLOGY — Hematogenous osteomyelitis occurs after a bacteremia, although the bacteremia is not
apparent in every case. Hematogenous osteomyelitis is usually monomicrobial [9,17-19]. S. aureus is the
most commonly isolated organism [20]. Aerobic gram-negative rods are identified in 30 percent of
cases. Salmonella osteomyelitis is well described among patients with sickle cell disease [20]. Pseudomonas
aeruginosa and Serratia marcescens are observed more frequently among intravenous drug users than other
patients [21].
• A number of unusual pathogens have been reported, especially in vertebral osteomyelitis,
including Mycobacterium tuberculosis [22], Candida species [23-25], Bartonella henselae [26], Coccidioides
immitis [27,28], and Cutibacterium (formerly Propionibacterium) acnes [29]. Beta-hemolytic streptococcal
osteomyelitis has occurred with increased frequency but remains relatively rare (<1 percent of cases) [30
]. Aspergillus osteomyelitis most commonly arises via a hematogenous mechanism and is frequently
associated with immune compromise [31].
• In general, the microbiology of hematogenous osteomyelitis is established via microbial culture, which may
be negative due to the inability to obtain the localized bacterial community during biopsy. In the future,
diagnostic studies using molecular techniques are likely to represent the microbiological characteristics of
hematogenous osteomyelitis more accurately.
• CLINICAL MANIFESTATIONS
• Hematogenous osteomyelitis — Local symptoms referable to bones are frequently
absent. Soft tissue findings may be more prominent than signs of bony involvement.
• Adults with vertebral osteomyelitis usually present with vague symptoms and signs
consisting of dull, constant back pain and spasm of the paravertebral muscles.
• Adults with vertebral osteomyelitis present with back pain that may be dull or
severe. (See "Vertebral osteomyelitis and discitis in adults".)
• Multifocal involvement may occur in intravenous drug users and patients with S.
aureus or beta-hemolytic streptococcal bacteremia.
• Abnormalities in routine laboratory tests such as elevation in white blood cell count,
sedimentation rate, and C-reactive protein are common but nonspecific
• Additional manifestations
• Brodie's abscess — A Brodie's abscess is a subacute or chronic osteomyelitis that occurs in the metaphysis
of long bones, typically the distal tibia but also reported in the femur, fibula, radius, and ulna [34]. It
generally occurs in patients <25 years of age [35]. It is usually of hematogenous origin but can also occur in
the setting of trauma. The infectious focus consists of an abscess confined within a rim of sclerotic bone.
• Patients typically present with the insidious onset of mild to moderate pain lasting for several weeks to
months in the absence of trauma, with or without periosteal elevation or fever. If the subacute process
progresses to chronic localized bone abscess, patients present with longstanding dull pain in the absence
of fever. The lack of systemic signs such as fever often leads to misdiagnosis of symptoms as bone
malignancy or sickle cell vasoocclusive pain crisis [36,37]. Radiography typically demonstrates a single
lesion near the metaphysis (image 1).
• 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
one-half of cases. Management should include surgical debridement with antibiotic therapy tailored to
culture findings.
• Sickle cell disease — The clinical presentation of osteomyelitis in
patients with sickle cell disease can be similar to symptoms of
vasoocclusive crisis (VOC). In general, infectious episodes are more
likely to be associated with temperature >102ºF (38.9ºC), persistent
pain, and decreased range of motion in the case of joint involvement.
Symptoms associated with both VOC and osteomyelitis include local
warmth, tenderness, and swelling.
• DIAGNOSIS — The diagnosis of hematogenous osteomyelitis requires a
high index of clinical suspicion; the diagnosis is established
radiographically and through microbial culture (blood culture or deep
bone biopsy).
• The earliest radiographic findings are soft tissue swelling, periosteal
thickening and/or elevation, and focal osteopenia. Destructive changes in
bone lag at least two weeks behind infection; approximately 50 to 75
percent of the bone matrix must be destroyed before plain radiographs
demonstrate lytic changes [38]. Subperiosteal collections,
myositis, and/or pyomyositis contiguous to a region of osteomyelitis are
most readily detected by magnetic resonance imaging (MRI).
• Distinguishing osteomyelitis from bone tumor can be difficult [39,40]. The penumbra sign, a thin
layer of granulation tissue lining a bone abscess cavity, may be seen in osteomyelitis (image 2). 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 [39]. (See
"Approach to imaging modalities in the setting of suspected osteomyelitis" and
"Vertebral osteomyelitis and discitis in adults".)
• In the absence of positive blood cultures together with radiographic findings consistent with
osteomyelitis, a bone biopsy or subperiosteal abscess aspirate for culture is needed. (See
"Overview of osteomyelitis in adults" and
"Approach to imaging modalities in the setting of suspected osteomyelitis".)
• The optimal diagnostic approach in patients with sickle cell disease is uncertain. Plain films, MRI, and
bone scintigraphy can demonstrate positive findings in vasoocclusive crisis (VOC) as well as
osteomyelitis [4,26-29]. A biopsy may not definitively rule out a VOC, especially if no infectious agent
is found [33]. Histopathology in both VOC and bony infection typically demonstrate an infiltrate of
neutrophils and macrophages as well as necrotic tissue.
• TREATMENT — If possible, antibiotic therapy should not be withheld prior
to obtaining culture from blood or deep bone biopsy. Empiric therapy can
be initiated followed by culture and sensitivity-directed antibiotics.
• Prompt diagnosis and initiation of appropriate antibiotic therapy (within
one month of symptom onset) increases the likelihood of resolution and
reduces the likelihood of recurrence [41]. Persistent symptoms >3 months
prior to management are associated with development necrotic bone and
devitalized tissue that act like a prosthetic implant, providing a devitalized
surface for microbial adherence, biofilm formation, and chronic disease.
These chronic infections are therapeutic challenge; thorough surgical
debridement is necessary in addition to antibiotic therapy.
• Antibiotics — Empiric antibiotic coverage should be directed at methicillin-resistant S. aureus (MRSA),
which is common even in community settings (table 1). Vancomycin (15 to 20 mg/kg/dose every 8 to
12 hours, not to exceed 2 g per dose) is typically used. Once an etiologic organism is isolated, the
antibiotic regimen should be tailored to susceptibility data [42].
• In intravenous drug users, empiric treatment should cover both S. aureus and gram-negative bacilli.
• In patients with sickle cell anemia, empiric therapy should cover S. aureus as well as Salmonella and
other gram-negative bacilli. In intravenous drug users, empiric treatment should cover both S.
aureus and gram-negative bacilli. Reasonable empiric treatment for both groups consists of
ciprofloxacin (750 mg orally or 400 mg intravenously every 12 hours) or other fluoroquinolone, in
addition to coverage outlined above for S. aureus.
• Hematogenous osteomyelitis in adults is frequently refractory to therapy, particularly if it involves
bones outside the spine and if debridement is not performed or if it is incomplete. The optimal
duration of therapy is uncertain. For patients with hematogenous (nonvertebral) osteomyelitis, at
least four weeks of parenteral antimicrobial therapy from the initiation of therapy or the last major
debridement surgery are warranted.
• Surgery — In hematogenous osteomyelitis, the nidus of infection is usually
within the medullary canal of the bone. Surgical intervention is warranted if
there is evidence of a persistent soft tissue abscess or subperiosteal
collection and/or if concomitant joint infection is suspected or diagnosed.
Surgical debridement is often both diagnostic and therapeutic, particularly in
patients who have negative blood cultures at the time the diagnosis is suspected.
• In adults with hematogenous osteomyelitis, a thorough intramedullary reaming
and unroofing is usually performed, with or without bone grafting. Debridement
of necrotic bone is often necessary in patients with sternoclavicular and pubic
osteomyelitis [43]. Soft tissues are reapproximated and the limb is protected by
external means (brace or cast) until the structural integrity of the bone is
reestablished by normal remodeling.
Treatment and prevention of osteomyelitis following trauma in
adults

• INTRODUCTION — Posttraumatic osteomyelitis refers to osteomyelitis that

develops as a result of contaminated open fractures or surgical treatment of
closed fractures [1,2]. Posttraumatic osteomyelitis can occur in up to 25
percent of open fractures; the risk depends upon the following factors [3-8]:
• ●Severity of fracture
• ●Severity of soft tissue injury
• ●Degree of bacterial contamination
• ●Presence of underlying vascular insufficiency (eg, peripheral vascular
disease or diabetes)
• ●Adequacy of surgical debridement
• MICROBIOLOGY — Microorganisms can be introduced directly into bone in the setting of trauma or via
contiguous spread from injury to overlying soft tissue. They proliferate in the presence of devitalized
tissues containing clotted blood and necrotic bone.
• Posttraumatic osteomyelitis pathogens in adults may include skin flora, soil organisms, or nosocomial
pathogens acquired in the hospital before, during, or after surgical intervention. Staphylococcus aureus,
coagulase-negative staphylococci, and aerobic gram-negative bacilli are the most common organisms;
other pathogens, including enterococci, anaerobes, fungi, and mycobacteria, have also been implicated [
5,9-15]. Similar microbiology is seen in children [16,17].
• Wound infections among combat casualties with tibial fractures have been associated with drug-resistant
aerobic gram-negative organisms, including Acinetobacter baumannii and Pseudomonas aeruginosa [18].
• Cultures obtained at the time of initial debridement do not always reflect the pathogens involved once
osteomyelitis has developed; the correlation is about 25 percent [19,20]. The reason for this observation is
likely multifactorial; 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 — Hallmarks of posttraumatic
osteomyelitis are nonunion of the fracture site and poor wound
healing after wound closure. Other symptoms may include fever and
local wound drainage, erythema, warmth, swelling, and pain.
• The tibia is the bone most frequently involved by posttraumatic
osteomyelitis, likely because it is the most common site of open
fracture given its lack of muscle covering and limited anastomotic
blood supply
• TREATMENT
• Initial fracture management — Initial management of fractures includes thorough irrigation and
debridement. There is no need for obtaining routine cultures of bone biopsies or fluid collections
obtained in the setting of superficial debridement of necrotic tissue. If subsequent debridement is
performed for suspected infection, culture collection (aerobic and anaerobic) is warranted at this time.
• Administration of antibiotics (as discussed below) and tetanus immunization are also warranted [1,2].
(See 'Antibiotic therapy' below.)
• The decision to use internal or external fixation for stabilization and union is made on a case-by-case
basis. Once union is achieved, fixation hardware should be removed (if possible) and additional
debridement performed. Final steps include bone grafting (if needed) and wound closure [23-33].
• Delay in wound closure is generally appropriate in Gustilo type II or III fractures (table 1). One review of
wound closure in open fractures suggests primary closure as an option for a specific subset of wounds
with no contamination, debrided within 12 hours, with good residual soft tissue that is easily
approximated, and good vascular supply
• Antibiotic therapy — Administration of parenteral antibiotics as soon as possible (ideally within six hours)
after open trauma is warranted to reduce the risk of soft tissue infection or osteomyelitis [1,21,35,36]. The
efficacy of prophylactic antibiotics was demonstrated in a meta-analysis including 913 patients with open
fractures [24]; use of prophylactic antibiotics was associated with an absolute reduction in infection of 0.08
(95% CI 0.04-0.12) with a number needed to treat of 13.
• In general, prophylactic antibiotic therapy should be directed against gram-positive organisms; for type III
fractures, additional gram-negative coverage should be added (table 1) [1,37]. In the setting of fecal or
potential clostridial contamination (eg, farm-related injuries), high-dose penicillin should be added. For open
fractures associated with water exposure, antibiotic therapy to cover pathogens such
as Aeromonas and Pseudomonas may be warranted. (See "Soft tissue infections following water exposure".)
• Cefazolin is a reasonable agent for gram-positive coverage; cefuroxime is an acceptable alternative. For
patients at risk for methicillin-resistant S. aureus (MRSA) (table 2), prophylactic antibiotics should include an
agent with activity against MRSA such as vancomycin. Reasonable agents for gram-negative coverage include
cephalosporins (late generation), extended-spectrum penicillins, or aminoglycosides (once-daily dosing) [
38,39]. Fluoroquinolones may have a detrimental effect on fracture healing and may be associated with
higher infection rates in type III open fractures when used as a single agent
• Antibiotic-impregnated beads placed in and around the fracture site may be useful as an adjunct to
systemic antibiotics for prevention or treatment of infection [40-44]. Data are most robust for
polymethylmethacrylate beads; these are typically removed within two to four weeks [11,45-51].
Antibiotic-impregnated calcium sulfate beads are absorbable; this approach has been used as a bone
substitute and delivery system for antibiotics repairing bony defects in open fractures caused by
combat-related injuries [44,52].
• The duration of prophylactic antibiotic therapy depends on the classification of the fracture (table 1)
[1,2,53,54]:
• ●For closed fractures, a single dose of antibiotics at the time of surgical repair is sufficient.
• ●For Gustilo type I and II open fractures, antibiotics may be discontinued after 24 hours.
• ●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 prophylactic antibiotics does not reduce the risk of infection and can
lead to the development of resistant organisms
• Established osteomyelitis — Management of established osteomyelitis or infected nonunion after an open
fracture requires debridement, bone biopsy culture to identify the causative microorganism(s), fracture
fixation (if needed), and antimicrobial therapy tailored to culture and susceptibility results [12,56,57]. Once
union is achieved, fixation hardware should be removed (if possible) and additional debridement performed.
Final steps include wound closure once the soft tissue over the area of bone trauma is fully healed [23-33].
• In the setting of localized osteomyelitis, surgical removal of involved bone may be possible without
compromising bony stability, while diffuse osteomyelitis requires complete resection of the bone for definitive
treatment. To achieve optimal union, antibiotic therapy for treatment of infection may need to be
administered with fixation hardware in place. Once union is achieved, fixation hardware can be removed,
followed by additional debridement, soft tissue coverage, and additional antibiotics in the absence of
hardware.
• If infected hardware must be retained indefinitely, long-term antibiotic suppression with an oral agent to
which the osteomyelitis pathogen is known to be susceptible may be warranted (following a full course of
parenteral therapy).
Clinical manifestations, diagnosis, and management
of diabetic infections of the lower extremities
• INTRODUCTION — Diabetic foot infections are associated with substantial morbidity
and mortality [1]. Important risk factors for development of diabetic foot infections
include neuropathy, peripheral vascular disease, and poor glycemic control. In the
setting of sensory neuropathy, there is diminished perception of pain and
temperature; thus, many patients are slow to recognize the presence of an injury to
their feet. Autonomic neuropathy can cause diminished sweat secretion resulting in
dry, cracked skin that facilitates the entry of microorganisms to the deeper skin
structures. In addition, motor neuropathy can lead to foot deformities, which lead to
pressure-induced soft tissue damage. Peripheral artery disease can impair blood flow
necessary for healing of ulcers and infections. Hyperglycemia impairs neutrophil
function and reduces host defenses. Trauma in patients with one or more of these
risk factors precipitates development of wounds that can be slow to heal and
predispose to secondary infection.
• OVERVIEW OF APPROACH TO THE PATIENT — In 2012, the Infectious Disease Society of America updated guidelines
on the diagnosis and management of diabetic foot infections, which were originally published in 2004 [2]. Practical
guidelines are also published regularly by the International Working Group on the Diabetic Foot [3]. The information
reviewed in this topic is largely consistent with these guidelines.
• The evaluation of a patient with a diabetic foot infection involves three key steps: 1) determining the extent and
severity of infection, 2) identifying underlying factors that predispose to and promote infection, and 3) assessing the
microbial etiology.
• The clinical history should focus on the details related to recent trauma, the duration of the current lesion(s),
associated systemic symptoms, and prior treatment, if any. Mechanical factors that may predispose to the formation
of an ulcer should be noted, and the history of blood glucose control should be assessed. Evidence of systemic
toxicity should also be carefully noted.
• Clinical examination should note the location of the lesions, extent of infection (eg, involving skin, subcutaneous
tissue, muscles, tendons and/or bone) and whether bone is grossly visible or palpable by probing. Although
osteomyelitis is highly likely if bone is visible, it may be present in the absence of such findings. (See
'Diagnosis of underlying osteomyelitis' below.)
• Clinical examination should also include a neurologic evaluation that documents the extent of sensory loss as well as
a vascular evaluation of the presence and severity of arterial and/orvenous insufficiency.
• Laboratory evaluation should include complete blood count as well as measurement of blood glucose,
electrolytes, and renal function. Baseline and subsequent inflammatory markers such as erythrocyte
sedimentation rate (ESR) and C-reactive protein (CRP) can be useful for monitoring response to therapy [4].
Some [5,6] but not all studies [7] have suggested that procalcitonin (PCT), a novel inflammatory marker,
may also be useful if laboratory facilities that test this substance are locally available; further investigation
is needed to determine the clinical utility of this assay. (See 'Diagnosis of underlying osteomyelitis' below.)
• Initial evaluation should include conventional radiographs to evaluate for bony deformity, foreign bodies,
and gas in the soft tissue. In select cases, magnetic resonance imaging (MRI) can be performed to better
evaluate for soft tissue abnormalities and osteomyelitis. (See 'Osteomyelitis' below and
"Approach to imaging modalities in the setting of suspected osteomyelitis".)
• Aerobic and anaerobic cultures of deep tissue or bone biopsies should be obtained at the time of
debridement if deep tissue infection or osteomyelitis is suspected. (See 'Obtaining samples for culture'
below.)
• If surgical intervention is warranted for management of infection, formal neurological and/or vascular
evaluation is important for determining the extent of surgical intervention. (See 'Surgery'below and
• MICROBIOLOGY — Most diabetic foot infections are polymicrobial, with up to five to seven different
specific organisms often involved. The microbiology of diabetic foot wounds is variable depending on the
extent of involvement [4,8-10]:
• ●Superficial diabetic foot infections (including cellulitis and infected ulcers in antibiotic-naïve individuals)
are likely due to aerobic gram-positive cocci (including Staphylococcus aureus, Streptococcus
agalactiae, Streptococcus pyogenes, and coagulase-negative staphylococci).
• ●Ulcers that are deep, chronically infected, and/or previously treated with antibiotics are more likely to be
polymicrobial. Such wounds may involve the above organisms in addition to enterococci,
Enterobacteriaceae, Pseudomonas aeruginosa, and anaerobes.
• ●Wounds with extensive local inflammation, necrosis, malodorous drainage, or gangrene with signs of
systemic toxicity should be presumed to have anaerobic organisms in addition to the above pathogens.
Potential pathogens include anaerobic streptococci, Bacteroides species, and Clostridium species [11-15].
• The typical microbiological spectrum also differs by geographic location, with gram-negative pathogens
predominating in the sub-tropical climates of Africa and Asia, in contrast to the predominantly gram-
positive organisms seen in the Western hemisphere
• Risk of specific organisms
• Resistant Staphylococcus aureus — Methicillin-resistant S. aureus (MRSA) is a
common pathogen in diabetic foot infections, particularly in those who have
had previous MRSA infections or known colonization. Other risk factors for
MRSA infection include prior antibiotic use, previous hospitalization, and
residence in a long-term care facility. (See
"Methicillin-resistant Staphylococcus aureus (MRSA) in adults: Epidemiology", sec
tion on 'Risk factors'
.)
• It is also important to note that diabetic patients with chronic foot wounds who
receive repeated and prolonged courses of antibiotics represent an important
risk group for development of vancomycin-intermediate S. aureus infections.
• Pseudomonas aeruginosa — P. aeruginosa is a particularly prevalent organism in diabetic foot infections
reported from regions with warm climates. As an example, in a study of 434 patients with infected
diabetic foot ulcers in Northern India, P. aeruginosa was the most common isolate, found in 20 percent of
initial cultures [18]. Macerated ulcers, foot soaking, and other exposure to water or moist environments
also likely increases the risk of involvement with P. aeruginosa. However, in temperate climates and in the
absence of the preceding findings and exposures, P. aeruginosa is a relatively uncommon pathogen [19].
Furthermore, its role as a pathogen in routine clinical practice is often hard to assess. As an example,
when P. aeruginosawas isolated from participants of clinical studies of diabetic foot infections, most
patients improved on antibiotic regimens that did not cover Pseudomonas, suggesting that it was not the
primary pathogenic organism [20,21].
• Resistant enteric gram-negative rods — Gram-negative bacilli that express an extended-spectrum beta-
lactamase (ESBL) are increasing in prevalence worldwide. These pathogens are more common in patients
with prolonged hospital stays, prolonged catheterization, prior antibiotic use, or residence in a long-term
care facility (see "Extended-spectrum beta-lactamases", section on 'Epidemiology'). The involvement of
ESBL-producing organisms in diabetic foot infections in particular is also increasingly reported
• CLINICAL MANIFESTATIONS — Diabetic foot infections can develop as a result of neuropathic or ischemic ulcers,
traumatic wounds, skin cracks or fissures, or other defects in the skin of the foot or nail beds (paronychia) [2,24].
Thus, infection can present as localized superficial skin involvement at the site of a preexisting lesion or as infection of
the skin or deeper skin structures that has spread beyond the site of local trauma. Such infections can subsequently
extend to joints, bones, and the systemic circulation [25].
• Diabetic foot infections are often accompanied by the cardinal manifestations of inflammation (erythema, warmth,
swelling, and tenderness) and/or the presence of pus in an ulcer or sinus tract [8]. However, these local signs of
infection may not be evident in all cases. Infections may not manifest with warmth and erythema in the setting of
severe ischemia. Diabetics with sensory neuropathy may have diminished sensation in the involved area and
therefore may not complain of tenderness nor, in some cases, even realize that infection is present. In such instances,
infection may progress to involve deeper tissues before the patient seeks clinical attention.
• Other local signs that may be present in diabetic foot infections are nonspecific and include nonpurulent drainage,
friable or discolored granulation tissue, and undermining of wound edges [2].
• Cutaneous bullae, soft tissue gas, skin discoloration, or a foul odor may occur in necrotizing infections. Findings of
gangrene, severe ischemia, or tissue necrosis may denote the presence of a limb-threatening infection.
• Systemic signs such as fever, chills, hypotension, and tachycardia may accompany local signs of infection, and their
presence indicates an increased severity of infection
• Osteomyelitis — Osteomyelitis can occur in the setting of a diabetic foot wound with or without
evidence of local soft tissue infection. Several clinical features are associated with the presence of
underlying osteomyelitis in patients with diabetic foot ulcers, including ulcer size >2 cm 2 and depth
allowing visibly exposed bone or ability to probe to bone [26-29]. The presence of a "sausage" toe,
with erythema and nonpitting edema that obliterates the normal contour of the digit, has been
associated with underlying osteomyelitis in diabetic patients, but the frequency of this finding is not
known [30].
• Although not specific or highly sensitive, the erythrocyte sedimentation rate (ESR) may be useful in
evaluating whether osteomyelitis is present. The finding of an ESR of 70 or greater increases the
clinical probability that osteomyelitis is present [28].
• On plain radiographs, findings characteristic of osteomyelitis include cortical erosion, periosteal
reaction, mixed lucency, and sclerosis [2,28]. There is often also evidence of soft tissue swelling.
However, radiographs may be normal or have only subtle non-specific findings early in infection.
Magnetic resonance imaging (MRI) findings of osteomyelitis include cortical destruction, bone
marrow edema, and soft tissue inflammation
• DIAGNOSIS — The diagnosis of a diabetic foot infection is primarily
based on suggestive clinical manifestations. The presence of two or
more features of inflammation (erythema, warmth, tenderness,
swelling, induration and purulent secretions) can establish the
diagnosis [2,31]. (See 'Clinical manifestations' above.)
• As many diabetic foot wounds are colonized by bacteria, the presence
of microbial growth from a wound culture in the absence of
supportive clinical findings is not sufficient to make the diagnosis of
infection
• Diagnosis of underlying osteomyelitis — The possibility of osteomyelitis should be considered in
diabetic patients with foot wounds associated with signs of infection in the deeper soft tissues and in
patients with chronic ulcers, particularly those overlying bony prominences that do not heal after
several weeks of wound care and off-loading. The diagnosis of osteomyelitis is definitively made through
isolation of bacteria from a sterilely obtained bone biopsy sample with histologic evidence of
inflammation and osteonecrosis [2,31]. However, bone biopsy is not always routinely available or
practical. In such instances, the presumptive diagnosis is based on clinical and radiographic assessment.
• Certain clinical findings can support the diagnosis of osteomyelitis. In two systematic reviews that
evaluated the diagnostic accuracy of exam findings in the setting of diabetic foot ulcers, the following
factors increase the likelihood of osteomyelitis [28,29]:
• ●Grossly visible bone or ability to probe to bone
• ●Ulcer size larger than 2 cm2
• ●Ulcer duration longer than one to two weeks
• ●Erythrocyte sedimentation rate (ESR) >70 mm/h
• If bone is grossly visible, supportive radiographic findings may not be necessary to make a
diagnosis of osteomyelitis. However, for diabetic patients with one or more of the other
above factors, a conventional radiograph with consistent changes can be helpful in making
the diagnosis of osteomyelitis and providing a baseline image useful for subsequent
management decisions. If the radiograph is indeterminate or normal and the diagnosis
remains uncertain, such patients should undergo magnetic resonance imaging (MRI), which
is highly sensitive and specific for osteomyelitis and superior to radiographs, three-phase
bone scans, and white blood cell scans [2,28,29,31,32]. (See 'Osteomyelitis' above.)
• In cases of diagnostic uncertainty based on clinical or radiographic features, failure of
empiric antibiotic therapy, planned hardware placement in potentially infected bone, and
mid- or hindfoot lesions that could lead to high-level amputations if inadequately treated,
obtaining a bone sample to establish diagnosis is recommended [2]. Culture of such bone
biopsy specimens is also important for identifying the causative organisms and their
susceptibilities in order to guide antimicrobial therapy.
• DIFFERENTIAL DIAGNOSIS — Other processes that lead to
inflammatory changes in the skin of the lower extremities can mimic
an infection. These include trauma, crystal-associated arthritis, acute
Charcot arthropathy, fracture, thrombosis, and venous stasis. Usually,
infection can be distinguished from these based on history, exam, and
imaging findings. However, infection may co-exist with other
inflammatory processes, and empiric antimicrobial therapy may be
warranted in some cases when the diagnosis is unclear
• DETERMINING SEVERITY OF INFECTION — Assessment of the severity of diabetic foot
infections is important for prognosis and to assist with management decisions (eg,
need for hospitalization, surgical evaluation, or parenteral versus oral antibiotic
therapy). In its 2004 guidelines on the diagnosis and treatment of diabetic foot
infections, the Infectious Diseases Society of America (IDSA) first outlined a clinical
classification scheme to define levels of severity (table 1) [4]. Briefly, it classifies
diabetic foot changes as uninfected, mild, moderate, and severe based on the extent
of inflammatory findings, the tissue depth involved, and the presence of signs of
systemic toxicity. The International Working Group on the Diabetic Foot published a
nearly identical classification system in 2012 [31].
• The prognostic value of such classification schema was assessed in a longitudinal
study of 1666 persons with diabetes; there was a trend toward increased amputation
risk among patients with more severe infections
• MANAGEMENT — Management of diabetic foot infections requires attentive wound
management, good nutrition, appropriate antimicrobial therapy, glycemic control, and
fluid and electrolyte balance. Although severe infections (table 1) warrant
hospitalization for urgent surgical consultation, antimicrobial administration, and
medical stabilization, most mild infections and many moderate infections can be
managed in the outpatient setting with close follow-up [12,21]. Hospitalization may be
needed for mild or moderate infections if the patient cannot manage glycemic control
at home, is unable to obtain or comply with proper wound care or offloading, needs
parenteral antibiotics and is unsuitable for outpatient parenteral antimicrobial therapy,
or needs more urgent diagnostic studies or surgical consultation [12,21].
• Several studies have reported improved outcomes with a multidisciplinary approach to
diabetic foot infections. This includes involvement of specialists in wound care,
infectious diseases, endocrinology, and surgery
• Wound management — Local wound care for diabetic foot infections typically includes debridement of callus and
necrotic tissue, wound cleansing, and relief of pressure on the ulcer [2,31].
• Sharp debridement, with the use of a scalpel or scissors to shear off necrotic tissue, is the preferred method to
remove callus and nonviable tissue. Such debridement promotes wound healing and removes pathogens that are
present in nonviable tissues [2]. However, enzymatic debridement may be preferable in patients with significant
vascular compromise that might impede the ability to heal new wounds created by sharp debridement [37]. As a
general rule, surgical intervention is needed for patients with extensive infection of subcutaneous or deeper
structures. (See "Management of diabetic foot ulcers", section on 'Debridement' and 'Surgery' below.)
• The purpose of wound dressing is to absorb exudate and create a moist environment to promote healing. A wide
array of dressing and wound healing products for ulcer management has been developed. These products include
enzymes, gels, hydrocolloids, honey and antiseptics containing iodine or silver salts. However, the efficacy of these
agents has not been evaluated or compared in carefully designed studies [24,38]. Avoidance of weight bearing is
generally more important than the specific type of wound dressing or ointment applied. (See
"Management of diabetic foot ulcers", section on 'Dressings'.)
• Off-loading the pressure on the diabetic foot wound is essential to wound care. Various devices to relieve pressure on
the foot are available, including casts and special shoes. The choice of device should be based on the wound location,
the severity of infection, and the presence of peripheral arterial disease.
• Obtaining samples for culture — Because microorganisms often colonize lower
extremity wounds regardless of the presence of a true infection, cultures should
be performed only in selected patients. If the clinical suspicion for infection is
low, samples from the wound should not be submitted for culture. In patients
with mild infection (table 1) in whom there is low suspicion for resistant
organisms (eg, no recent antibiotic course), wound culture is often not necessary.
However, wound culture is often helpful in cases of moderate or severe infection
(table 1) and when the concern for multidrug-resistant organisms is high. Ideally,
samples for culture should be obtained prior to the initiation of empiric
antibiotics. However, in cases of systemic toxicity or limb-threatening infections,
antibiotic therapy should not be withheld before surgical cultures are obtained.
•.
• The preferred clinical specimens for reliable culture include aspirate from an abscess or
curettage from the ulcer base following superficial debridement of necrotic tissue.
Organisms cultured from superficial swabs are not reliable for predicting the pathogens
responsible for deeper infection [39-42]. (See "Overview of osteomyelitis in adults".)
• In the setting of osteomyelitis, bone biopsy is the preferred method of sample collection
for culture. If performed percutaneously, sampling through uninvolved tissue under
radiographic guidance is preferred. Although sinus tract cultures may be of some use for
prediction of osteomyelitis if S. aureus or Salmonella species are identified, in general,
such cultures are not worthwhile [43,44]. (See 'Diagnosis of underlying osteomyelitis'
above and "Overview of osteomyelitis in adults", section on 'Bone biopsy'.)
• Samples should be sent for both aerobic and anaerobic bacterial cultures
• Surgery — Consultation with a surgeon with experience in diabetic foot infections is
important for cases of severe infections and in most cases of moderate infections.
Surgical debridement is required for cure of infections complicated by abscess,
extensive bone or joint involvement, crepitus, necrosis, gangrene or necrotizing
fasciitis and is important for source control in patients with severe sepsis [2,45,46].
The utility of early surgical debridement was illustrated in a retrospective review of
112 diabetic patients with severe foot infections [45]. Those patients who underwent
surgical intervention at the time of presentation had a significantly lower rate of
above-ankle amputation than those who received three days of intravenous
antimicrobial therapy prior to surgery.
• In addition to surgical debridement, revascularization (via angioplasty or bypass
grafting) and/or amputation may be necessary. Determination of the extent of
surgical intervention required should be guided by vascular evaluation
• Antimicrobial therapy — Empiric antibiotic therapy should be selected based on the
severity of infection and the likelihood of involvement of resistant organisms. (See
'Determining severity of infection' above and 'Microbiology' above.).
• Subsequent antibiotic therapy should be tailored to culture and susceptibility results.
However, it is not always necessary to cover all microorganisms isolated from
cultures [4].
• Patients with ulcerations that are not infected should not receive antibiotic therapy [
47,48]. However, such patients often benefit from local wound care and measures
that reduce the pressure at the site of ulceration.
• Our treatment approach outlined below is consistent with the Infectious Diseases
Society of America (IDSA) guidelines on the diagnosis and treatment of diabetic foot
infections and is based on their classification scheme for severity of infection
• In general, the limited data on antibiotic therapy of diabetic foot infections do
not allow comparison of outcomes of different regimens [2,31]. On the basis
of the available observational studies and randomized trials, no single drug or
combination appears to be superior to others [49-51]. In a systematic review
of 12 studies comparing antibiotic regimens for lower extremity skin and soft-
tissue infections in diabetic patients, reported clinical cure rates ranged from
48 to 90 percent [50]. None of the studies demonstrated a significant benefit
for any specific antibiotic agent. However, subsequent data suggest that
tigecycline, specifically, may not be effective as other regimens; it resulted in
lower clinical cure rates and did not meet prespecified non-inferiority criteria
compared with ertapenem with or without vancomycin in a randomized,
double-blind trial of patients with diabetic foot infections
• Empiric therapy
• Mild infection — Mild diabetic foot infections can be treated with outpatient
oral antimicrobial therapy. Empiric therapy of patients with mild infections
should include activity against skin flora including streptococci and S. aureus.
Agents with activity against methicillin-resistant S. aureus (MRSA) should be used
in patients with purulent infections and those at risk for MRSA infection (see
'Resistant Staphylococcus aureus' above). Appropriate agents are outlined in the
table (table 2).
• Patients who fail to respond to treatment with agents active against streptococci
and methicillin-susceptible S. aureus should receive extended antimicrobial
coverage to include activity against MRSA, aerobic gram-negative bacilli, and
anaerobes
• Moderate infection — Empiric therapy of deep ulcers with extension to fascia should
include activity against streptococci, S. aureus (and MRSA if risk factors are present), aerobic
gram-negative bacilli and anaerobes and can be administered orally in many cases.
Appropriate regimens are outlined in the table (table 2). Patients presenting with extensive
infections that involve deep tissues should receive empiric parenteral therapy with activity
against the above pathogens (table 3). Empiric coverage for P. aeruginosa may not always
be necessary unless the patient has particular risk for involvement with this organism, such
as a macerated wound or one with significant water exposure. (See
'Pseudomonas aeruginosa' above.)
• Severe infection — Limb-threatening diabetic foot infections and those that are associated
with systemic toxicity should be treated with broad-spectrum parenteral antibiotic therapy.
In most cases, surgical debridement is also necessary. Empiric therapy should include
activity against streptococci, MRSA, aerobic gram-negative bacilli, and anaerobes.
Appropriate regimens are outlined in the table
• Targeted therapy — If appropriate wound cultures were submitted, antimicrobial
therapy should be tailored to culture and susceptibility results when available.
However, it is not always necessary to cover all microorganisms isolated from
cultures [2,31]. Virulent species such as S. aureus and streptococci (group A or B)
should always be covered, but in polymicrobial infections, less virulent organisms
(such as coagulase negative staphylococci and enterococci) may be less
important. Furthermore, if isolates are resistant to an empiric regimen to which
the patient is clearly responding well, broadening the spectrum to include those
isolates may not be necessary. On the other hand, if the patient is not responding,
expanding therapy to target all isolated organisms may be warranted.
• For those patients who were initiated on parenteral therapy, a switch to an oral
regimen is reasonable following clinical improvement
• Duration of therapy — The duration of antibiotic therapy should be tailored to individual
clinical circumstances. Patients with mild infection should receive oral antibiotic therapy in
conjunction with attentive wound care until there is evidence that the infection has resolved
(usually about one to two weeks). Antibiotics need not be administered for the entire
duration that the wound remains open [2,31].
• Patients with infection also requiring surgical debridement should receive intravenous
antibiotic therapy perioperatively. In the absence of osteomyelitis, antibiotic therapy should
be administered in conjunction with attentive wound care until signs of infection appear to
have resolved (two to four weeks of therapy is usually sufficient). If there is a good response
to parenteral therapy, oral agents can be used to complete the course of treatment [54].
• Patients requiring amputation of the involved limb should receive intravenous antibiotic
therapy perioperatively. If the entire area of infection is fully resected, a brief course of oral
antibiotic therapy (about a week) following surgery is usually sufficient
• Osteomyelitis — Similar to other types of diabetic foot infections, no data support the
superiority of specific antimicrobial agents for osteomyelitis [50]. Appropriate regimens for
empiric therapy are similar to that for moderate to severe diabetic foot infections (table 3).
• Targeted antimicrobial therapy should be tailored to culture and sensitivity results, ideally
from bone biopsy. In one retrospective study of diabetic patients with osteomyelitis of the toe
or metatarsal head, remission (absence of signs of infection and no need for surgery after one
year) was more likely in the 22 patients treated with regimens guided by bone biopsy data
compared with the 28 treated based on swab culture data (82 versus 50 percent) [55]. Of
note, those who had bone culture were also more likely to be treated with a rifampicin-
containing regimen, which likely was a confounding variable and limits the interpretation of
this finding.
• For those patients who were initiated on parenteral therapy, a switch to an oral regimen is
reasonable following clinical improvement. Antibiotic therapy for osteomyelitis is discussed in
detail elsewhere.
• Many patients with osteomyelitis of the foot benefit from surgical resection.
In a systematic review of studies evaluating treatment of diabetic foot
osteomyelitis, there was no study that directly compared surgical
intervention to nonsurgical management [56]. However, studies of prolonged
antibiotic therapy without resection reported success rates comparable to
those reported with surgery, about 60 to 90 percent. Furthermore, partial
amputations of the foot (eg, ray or transmetatarsal amputations) may
adversely alter the biomechanics of the foot, increasing the risk of future
ulceration. Thus, in certain cases, limited surgical debridement combined
with prolonged antibiotic therapy may be appropriate [2,31]. However,
extensive surgical debridement or resection is preferable in the following
clinical circumstances
• Persistent sepsis without an alternate source
• ●Inability to receive or tolerate appropriate antibiotic therapy
• ●Progressive bone deterioration despite appropriate antibiotic
therapy
• ●Mechanics of the foot are compromised by extensive bony
destruction requiring correction
• ●Surgery is needed to achieve soft tissue wound or primary closure
• The duration of antibiotic therapy of osteomyelitis depends on the
extent of residual affected tissue. If all infected and necrotic bone and
soft tissue has been resected (eg, amputation), then a brief course (ie,
about a week) of antibiotics is likely adequate. Otherwise, the optimal
duration is uncertain. Four to six weeks is an appropriate course if
there is residual infected bone following debridement of necrotic
bone. However, if necrotic bone remains, clinical cure may require
several months of antibiotic therapy.
• Adjunctive therapies — Adjunctive therapies for treatment of diabetic
foot infections include vacuum-assisted wound closure, hyperbaric
oxygen and granulocyte colony-stimulating factor (G-CSF) [57-59].
• Of these, vacuum-assisted wound closure is used most frequently. In a
randomized trial evaluating vacuum-assisted wound closure including
342 patients with diabetic foot ulcers, complete ulcer closure was
achieved more often among those who used vacuum-assisted closure
than those who did not (43 versus 29 percent, respectively) [57].
Vacuum-assisted closure and hyperbaric oxygen therapy are discussed
in detail separately.
• The role of G-CSF in managing diabetic foot infections is not clear. In a meta-
analysis of five trials that included 167 patients, there was a reduction in the
rates of surgical intervention and amputation, specifically, associated with
the use of G-CSF (relative risks 0.38 [95% CI 0.21 to 0.70] and 0.41 [95% CI
0.18 to 0.95], respectively, compared with no G-CSF) and no significant
difference in adverse effects [60]. There was no clear benefit to G-CSF with
regards to infection resolution or improvement. The included studies were all
of small size, and there was substantial clinical heterogeneity across studies,
including variable antibiotic regimens used, G-CSF formulations and doses,
and severity of underlying infection. Additional data are needed before G-CSF
can be recommended or its high cost can be justified for use in diabetic foot
infections.
• Follow-up — Close follow-up is important to ensure continued improvement and to
evaluate the need for modification of antimicrobial therapy, further imaging, or
additional surgical intervention. Wound healing and a decrease in previously elevated
inflammatory markers can be signs of clinical resolution, and may be particularly
helpful in cases of osteomyelitis. If clinical evidence of infection persists beyond the
expected duration, issues of patient adherence to therapy, development of antibiotic
resistance, an undiagnosed deeper infection (eg, abscess or osteomyelitis), or
ischemia should be evaluated [4].
• If infection in a clinically stable patient fails to respond to more than one antibiotic
course, some favor discontinuing antimicrobial therapy to optimize the yield of
culture specimens obtained a few days later [4]. In general, this is a safe and
reasonable approach, although deep cultures are often positive even if therapy is
continued up to the time of debridement.