What The Literature Reveals About Diabetic Foot Osteomyelitis

Given that osteomyelitis in the diabetic foot can lead to complications such as limb loss, ensuring a proper diagnosis and timely treatment is vital. Accordingly, this author surveys the literature to review pertinent classification systems, the merits of different imaging techniques and current thoughts on the debate over conservative therapy versus surgical treatment.

   The worldwide incidence of diabetes has reached nearly epidemic proportions. With this increased incidence, there has been a significant rise in the comorbidities commonly associated with the disease process in patients living with diabetes.

   Diabetic foot ulcerations (DFUs) are a common complication. Researchers have estimated that people with diabetes have as high as a 25 percent lifetime risk of developing a DFU.1,2 In addition to the development of DFUs, greater than 50 percent of these ulcerations will become infected. This would account for nearly 20 percent of all diabetes-related hospital admissions and therefore a significant portion of healthcare-related costs. This amounted to nearly $11 billion in 2001.3-9

   In those patients presenting with infected diabetic ulcerations, underlying osteomyelitis is present in as many as 65 percent of patients, and these infected ulcerations present a major risk factor for non-traumatic lower extremity amputation (LEA).10

   It has been well documented that the consequences of major lower extremity amputation are severe with the estimated five-year survival rate following surgery being less than 50 percent.11 In fact, this data suggests that the mortality rate associated with diabetic LEAs is greater than most cancers.11 It is therefore vital to provide early and effective diagnosis, and management of patients presenting with diabetic ulcerations, especially those presenting with concomitant osteomyelitis, in order to avoid potential limb loss.

A Guide To Classification Systems For Osteomyelitis

   Osteomyelitis can generally be defined as any inflammatory process in bone that is caused by microorganism infection.12,13 Persistent involvement of the osseous structures, which is often accompanied by clinical signs of inflammation, can yield osseous fragmentation and overall destruction of the skeletal architecture.14-16

   There have been numerous attempts to classify osteomyelitis and perhaps Waldvogel presented the most recognized classification, in which he classified osteomyelitis according to etiology.17 This classification system grouped osteomyelitis into one of three clinical categories: hematogenous osteomyelitis, osteomyelitis associated with a contiguous focus and chronic osteomyelitis.

   Hematogenous osteomyelitis most commonly occurs in pediatric patients although this type of osteomyelitis is presenting in increasing numbers of elderly and immunocompromised patients. In this cohort, the bone infection begins with bacteria seeded from the blood. This most commonly occurs in the metaphyseal region of long bones.

   Osteomyelitis associated with a contiguous focus most commonly occurs in patients presenting with lower extremity ulceration and, by extension, those patients with diabetes whom we see most frequently. In this cohort, bacterial inoculation into bone occurs from an external source such as a penetrating traumatic injury with contaminated objects, infection following implant placement or in patients with persistent overlying soft tissue infection. This type of osteomyelitis can affect any age group and is the most commonly observed overall.

   Chronic osteomyelitis can originate from either a hematogenous or contiguous focus, and is often associated with increasing antibiotic resistant microorganisms.15

   Other authors have described classification systems. For example, Buckholz sought to classify osteomyelitis according to pathophysiology and developed seven different types of observable osteomyelitis.18 However, both Buckholz and Waldvogel’s descriptive classification systems yielded no specific resultant treatment algorithms.

   Recognizing this, Cierny and Mader developed a descriptive classification system to emphasize the clinical aspects of treating patients with osteomyelitis and to foster development of more focused treatment algorithms.19,20 The Cierny-Mader classification is based primarily on the anatomy of bone infection, which is divided into four stages, and the physiology of the host, which is subdivided into categories of increasing disease states (see “A Pertinent Overview Of The Cierny-Mader Classification” on page 76).

   Establishing a classification that combines anatomic extent and patient morbidity allows for the development of comprehensive management guidelines, which are reportedly effective in the management of osteomyelitis of long bones. Despite the strengths of the Cierny-Mader classification, researchers have demonstrated that it is less useful for classifying osteomyelitis of the small bones in the foot.12,20

Key Insights On The Microbiology Of Diabetic Osteomyelitis

   Lower extremity infections in patients with diabetes are frequently polymicrobial and the microbiology of diabetic osteomyelitis in the lower extremity follows this trend.21 Lavery and Sariaya demonstrated that osteomyelitis of the foot in patients with diabetes was polymicrobial in 83 percent of patients with an average of 2.25 pathogens per patient.22

   Staphylococcus aureus, Staphylococcus epidermidis, Enterococcus and Streptococcus species were most commonly isolated from bone culture.21 However, researchers also found aerobic gram-negative rods (Pseudomonas aeruginosa being the most common) and obligate anaerobe species in many cases.21 In this age of increasing drug-resistant organisms, physicians are seeing methicillin-resistant Staphylococcus aureus (MRSA) more commonly, especially in patients with diabetes.

What Clinical Signs Should Raise Suspicion Of Osteomyelitis?

   When a patient presents with a lower extremity infection, physicians should evaluate the site, size and character of the wound. One should determine whether there is exposed bone or joint involvement, and check for the presence of sinus tracts, abscess formation or extension along fascial planes. One study demonstrated that ulcerations with an area of 2 cm2 and depths of 3 mm were more likely to have underlying osteomyelitis.23

   There have been numerous attempts at developing wound classification systems to assist the clinician in describing diabetic ulcerations. The University of Texas (UT) wound classification system is widely utilized and provides a uniform basis for describing lower extremity diabetic ulceration with regard to the depth of wound and the presence (or absence) of ischemia and infection.24-26 Extending from grade 0 to grade 3, the UT system describes the depth of the wound and further stages wounds according to the presence of infection, ischemia or both.

   Studies have demonstrated the validity of the UT classification system and described poor overall outcomes in patients who present with higher stage and grade ulcerations.24

   The diagnosis of osteomyelitis is not always straightforward. Often, a combination of clinical presentation, laboratory data, radiographic imaging and analysis of biopsy culture data is required to identify osteomyelitis adequately and establish appropriate treatment plans. When faced with UT grade 2a-3a or greater wounds, the presence of exposed bone or joint in the wound raises the clinical suspicion for osteomyelitis in a patient with diabetes.

Assessing The Merits Of The Probe To Bone Test

   In 1995, Grayson, et al., reported that a positive “probe to bone” (PTB) test in patients with infected ulcerations was highly predictive for a diagnosis of osteomyelitis.27,28 However, one should recognize that this study model was designed for use in the management of severe limb-threatening infections. For these particular patients, the overall prevalence of osteomyelitis was nearly 66 percent, which is greater than the prevalence one would see in the normal population of patients with diabetic ulcerations.

   More recently, Lavery, et. al., challenged the validity of the Grayson PTB test. In their patient series, they determined that while a positive PTB demonstrated 87 percent sensitivity, the predictive value of this test for osteomyelitis was only 57 percent.29 Furthermore, considering that researchers performed this study on a predominately outpatient population, the overall prevalence of osteomyelitis in this group was approximately 12 percent, much less than what was reported by Grayson and colleagues.27

   In their study, Lavery, Armstrong, et. al., determined that a negative PTB test demonstrated a negative predictive value of approximately 91 percent and a negative PTB test would reliably exclude the diagnosis of ostemyelitis.29

   Clearly, the patient population is a factor with the PTB test. In those patient groups in which the prevalence of osteomyelitis is high, as in patients with severe limb-threatening infections, a positive PTB is more likely to indicate the presence of bone infection. Conversely, in the outpatient setting, a mild to moderately infected wound with a positive PTB may not necessarily indicate osteomyelitis. Regardless, further evaluation to confirm the diagnosis is warranted. In other words, it is the pre-test probability of having osteomyelitis that determines whether the PTB test will be valuable.

What You Should Know About Wound Cultures And Bone Biopsies

   When a patient with diabetes presents with lower extremity ulceration, physicians often obtain a wound culture. However, there is much debate on the usefulness of initial wound culture data in the diagnosis of osteomyelitis. While there is certainly a need to determine causative organisms present in osteomyelitis in order to appropriately tailor antibiotic therapy, research has demonstrated that superficial swab cultures from infected ulcers are significantly unreliable in determining bone pathogens.4

   One study demonstrated that superficial swabs of infected ulcerations identified deep soft tissue pathogens in only 75 percent of cases and bone pathogens in less than 30 percent.30 In fact, in this study, deep soft tissue specimens did not correlate with bone specimens. Lavery and Sariaya found that only 36 percent of soft tissue cultures yielded accurate bone pathogens.22 Given this disparity, it is recommended that one obtain bone biopsy specimens in addition to deep soft tissue cultures to increase the likelihood of accurately identifying the appropriate causative microorganisms.

   Bone biopsy has long been considered the gold standard in the diagnosis of osteomyelitis. It reportedly offers a sensitivity of 95 percent and a specificity of 99 percent.16 Authors vary in their description of how to obtain bone biopsy samples and have employed multiple methods, including surgical excision and computerized tomography (CT) guided or fluoroscopic guided core biopsy.30

   When it comes to bone biopsy in the diabetic foot, one should pursue a histologic examination as well as gram stain and culture. Histologically, evidence of osteomyelitis will appear as osseous fragmentation, necrosis and increased numbers of both acute and chronic inflammatory cells.14,16,23 Bone biopsy allows the clinician vital culture and antimicrobial susceptibility data that is useful in guiding antibiotic therapy.

Essential Insights On Imaging

   In addition to laboratory studies, various imaging modalities, including nuclear bone and leukocyte-labeled scans, MRI, CT and plain film radiographs, have become increasingly useful in the diagnosis of osteomyelitis in the patient with diabetes.

   Plain film radiographs are recommended as the initial imaging test to evaluate for pedal osteomyelitis. The radiographs can demonstrate cortical changes, osteolysis, periosteal reaction and focal osteopenia.31 Note that these changes are not apparent acutely and they present 10 to 20 days after infection.32

   Studies have demonstrated that plain film radiographs have a sensitivity of 60 percent and a specificity of 80 percent in diagnosing acute osteomyelitis.33-35 However, considering the delay prior to the presentation of radiographic changes, serial radiographs may be necessary in those instances in which the diagnosis of osteomyelitis is uncertain.36

   One can utilize nuclear medicine scans in the diagnosis of osteomyelitis of the lower extremity. However, studies have demonstrated that this modality's role may be limited due to the inability to distinguish accurately between neuropathic Charcot osteoarthropathy and osteomyelitis.37,38 Nuclear medicine scans are more sensitive than plain film radiography or magnetic resonance imaging (MRI) in detecting neuroarthropathy, especially when evaluating early pre-radiographic changes for these patients.31

   Researchers have shown that white blood cell labeled scans are more sensitive for detecting osteomyelitis (90 percent). However, the specificity can be limited (70 to 80 percent) due to coexisting pathology such as cellulitis, a common concomitant finding in patients with diabetic osteomyelitis.39

   More recently, fluorodeoxyglucose positron emission tomography (FDG-PET) has shown promise in the diagnosis of osteomyelitis in the patient with diabetes.38,40 Fluorodeoxyglucose is an indicator of cellular metabolism, which accumulates at sites of infection. When using shorter duration study times, one can visualize this with higher resolution ratios than current metabolic procedures.41

   Despite these benefits, FDG-PET scans are of limited diagnostic value because FDG will accumulate in a number of disease processes, such as neoplasm, that demonstrate increased metabolic activity.

   Despite this, recent studies that included PET/CT evaluation in patients with diabetes suspected of osteomyelitis demonstrated accurate differentiation between osteomyelitis, cellulitis and neuropathic osteoarthropathy.42,43 Despite the overall lower specificity of nuclear medicine scans in the diagnosis of osteomyelitis, these modalities do have a role in evaluating those patients in which MRI is contraindicated. However, these scans are relatively expensive, technically demanding and time-consuming.36

   Practitioners do not routinely utilize CT scans to evaluate osteomyelitis and often use it only when MRI is contraindicated. Despite this, CT definitely has a role in the evaluation of neuropathic osteoarthropathy and soft tissue swelling in the absence of an ulcer, in which fat stranding or focal collections may occur. Necrotizing fasciitis is an example of this.31

   Magnetic resonance imaging (MRI) is the modality of choice for evaluating osteomyelitis in the lower extremity. Recent studies have suggested that MRI demonstrates sensitivity of 90 percent and specificity of 83 percent.44 Enderle, et al., reported positive and negative predictive values of 93 percent and 100 percent respectively.35

   Unlike previously discussed imaging modalities, MRI can provide significant anatomic detail of the soft tissue and osseous structures one is evaluating. In addition, MRI can reveal bone marrow edema associated with inflammation, subperiosteal abscess formation and may aid in early detection of bone infection. Although MRI is expensive, it provides earlier detection of osseous changes in osteomyelitis as well as excellent anatomic detail that allows delineation of necrotic and infected tissue from healthy tissue. This gives the surgeon the ability to plan for tissue sparing resection of infected bone, which is vital in these limb salvage patients.45

Underscoring The Challenges Of Managing Diabetic Osteomyelitis

   Patients with diabetic osteomyelitis provide a significant management challenge due to concomitant risk factors and disease processes that complicate any potential course of treatment.3,10,14,36,46,47 In addition to having diabetes, these patients often present with elements of vascular compromise and neuropathy. Accordingly, a triad of disease leads to ulceration, infection and limb loss.

   Therefore, it is vital that the patient’s overall medical status be optimal in the management of diabetic osteomyelitis to provide the greatest likelihood for a positive outcome. The patient’s vascular status is critical to the successful management of diabetic osteomyelitis. In those instances in which one identifies vascular pathology, the patient must undergo rapid revascularization by either open or endovascular means.48,49

   To manage these complex patients appropriately, one must address risk factors such as hyperglycemia, poor nutritional status and nephropathy. For these reasons, an interdisciplinary team approach to the management of these complicated patients is recommended.50 Numerous studies have demonstrated the increased efficacy of such interdisciplinary models and research has demonstrated that improved outcomes follow when providers can work together to optimize the speed and quality of patient care.10,47,51-53

Current Concepts In Debating Conservative Management And Surgical Resection

   When it comes to the management of diabetic osteomyelitis, treatment options are either conservative or surgical. Conservative medical management consists of limited to no debridement with the focus of the therapy directed at long courses of parental antibiotics. There is some discussion as to which patients should receive conservative therapy.

   Therefore, in an attempt to provide more standardization regarding treatment protocols, the Infectious Diseases Society of America (IDSA) developed a paradigm to identify those patients for whom conservative medical therapy would be appropriate.54 The IDSA notes the following indications for conservative medical treatment of diabetic osteomyelitis.

   1) There is no acceptable surgical target.
   2) The patient has ischemia caused by non-bypassable vascular disease but seeks to avoid amputation.
   3) Infection is confined to the forefoot and there is minimal soft tissue loss.
   4) Surgical management carries excessive risk or is otherwise not appropriate nor desirable.7

   Often, such therapy consists of six to eight weeks of intravenous (IV) therapy followed by a course of oral antibiotics. However, there is limited literature to support a specific protocol for the duration of treatment necessary to eradicate osteomyelitis via these conservative means.5,36 Generally speaking, empiric antibiotic therapy, such as clindamycin, imipenem/cilastatin (Primaxin, Merck), fluoroquinolones, cephalosporins, linezolid (Zyvox, Pfizer) and penicillin/b-lactamase inhibitor combinations, have shown clinical effectiveness.5,36 After obtaining culture and sensitivity data, one should titrate antibiotic coverage appropriately.

   While early attempts at management of osteomyelitis with conservative therapies alone yielded poor results, some clinicians suggest that advances in imaging such as MRI are allowing for earlier diagnosis and that early stage osteomyelitis may be more amenable to antibiotic therapy alone.55 Researchers have presented several case series and remission rates in these cases utilizing antibiotic therapy alone vary from 25 to 88 percent.16,56 However, considering the variability with patient population and antibiotic regimen inherent within the studies, further research is necessary.

   While studies have demonstrated success in the treatment of osteomyelitis with parental antibiotic therapy alone, more optimal management likely involves a combination of antibiotics and early, appropriate surgical debridement. Indeed, many authors suggest that osteomyelitis is a “surgical disease,” maintaining that surgical intervention should be part of primary treatment.10,57-59

   One study from 1996 compared two cohorts of diabetic patients with osteomyelitis and demonstrated a 57 percent cure rate with antibiotics alone in comparison to a 78 percent cure rate with the addition of conservative surgery.60 Additionally, one should be aware that the duration of antibiotic therapy, in this study, was significantly reduced in the conservative surgery group.

   There is a consensus within the literature to support the combination of focused, culture-guided medical management in combination with surgical resection although a discussion persists regarding the degree of resection necessary.4,16,55 Obviously, the focus must remain on eradication of osseous involvement while attempting to maintain appropriate foot function in order to allow for ambulation and transfers. However, biomechanical considerations alone should not limit the surgeon to performing a resection that is too limited.

   Attinger, et al., recommend aggressive surgical debridement and others have suggested performing the surgical approach to osteomyelitis with wide excision of necrotic and infected bone.61,62 Research has demonstrated a clearance of 5 mm or greater at the margins to reduce the risk of recurrence in cases of chronic osteomyelitis in comparison to groups with minimal marginal resections.63 Regardless, it is vital that the surgeon critically evaluate the reasonable functional outcome for the patient following resection or possible distal amputation to determine the future risk for complications or deformity.57,62,64

In Summary

   Osteomyelitis in patients with diabetes can present the clinician with a number of management challenges. These patients often present with concomitant vascular disease and neuropathy that combine to increase the risk of ulceration and subsequent lower extremity infection. These infections serve as the major admitting diagnosis in patients with diabetes in the United States. In addition to lower extremity soft tissue infection, these patients often demonstrate underlying osteomyelitis, which is a major risk factor leading to non-traumatic lower extremity amputation.

   It has been said that every 30 seconds, a limb is lost in the world due to diabetes. Many of these limbs are lost due to diffuse soft tissue infection and osteomyelitis. Clearly, it is necessary for surgeons involved in limb salvage to determine appropriate treatment regimes to manage both lower extremity cellulitis as well as osteomyelitis in order to prevent this epidemic of amputation.

   Advances in imaging technology have allowed more rapid diagnosis but these techniques remain expensive and are not universally available. Bone biopsy remains the gold standard diagnostic test. In addition to providing histiologic confirmation of the diagnosis, bone biopsy provides culture and sensitivity data, which can help physicians direct appropriate antibiotic therapy as a part of the overall treatment regimen.

   While some authors contend that physicians can manage osteomyelitis appropriately via conservative means, most would agree that conservative therapy alone should be limited to those patients who cannot undergo surgical debridement. The literature has shown that a combination of surgical resection and antibiotic therapy is most effective. In those instances in which one is utilizing surgical resection, it is important for the surgeon to evaluate realistic functional outcomes for the patient following surgery. This enables the surgeon to create the best residual extremity for ambulation and transfer while reducing the risk of further ulceration and amputation.

Dr. Fitzgerald is a third-year surgical resident at the Washington Hospital Center in Washington, DC. After his residency, he will be the 2009-2010 Diabetic Limb Salvage Fellow at the University of Arizona. One may contact him at Dr.Ryan.Fitzgerald@gmail.com.

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