Oxford Journals>Medicine>Clinical Infectious Diseases>Volume 39, Issue 7>Pp. 885-910.


Diagnosis and Treatment of Diabetic Foot Infections

Benjamin A. Lipsky1,a, Anthony R. Berendt2,a, H. Gunner Deery3, John M. Embil4, Warren S. Joseph5, Adolf W. Karchmer6, Jack L. LeFrock7, Daniel P. Lew8, Jon T. Mader9,b, Carl Norden10, and James S. Tan11

- Author Affiliations
1.    Medical Service, Veterans Affairs Puget Sound Health Care System, and Division of General Internal Medicine, Department of Medicine, University of Washington School of Medicine, Seattle, Washington
2.    Bone Infection Unit, Nuffield Orthopaedic Centre, Oxford, United Kingdom
3.    Northern Michigan Infectious Diseases, Petoskey, Michigan
4.    Section of Infectious Diseases, Department of Medicine, University of Manitoba, Winnipeg, Manitoba
5.    Section of Podiatry, Department of Primary Care, Veterans Affairs Medical Center, Coatesville, Pennsylvania
6.    Division of Infectious Diseases, Department of Medicine, Harvard Medical School, and Beth Israel Deaconess Medical Center, Boston, Massachusetts
7.    Dimensional Dosing Systems, Sarasota, Florida
8.    Department of Medicine, Service of Infectious Diseases, University of Geneva Hospitals, Geneva, Switzerland
9.    Department of Internal Medicine, The Marine Biomedical Institute, and Department of Orthopaedics and Rehabilitation, University of Texas Medical Branch, Galveston, Texas
10.   Department of Medicine, New Jersey School of Medicine and Dentistry, and Cooper Hospital, Camden, New Jersey
11.    Department of Internal Medicine, Summa Health System, and Northeastern Ohio Universities College of Medicine, Akron, Ohio

Reprints or correspondence: Dr. Benjamin A. Lipsky, Veterans Affairs Puget Sound Health Care System, S-111-GIMC, 1660 S. Columbian Way, Seattle, WA 98108-9804 (This email address is being protected from spambots. You need JavaScript enabled to view it.).
Executive Summary
1. Foot infections in patients with diabetes cause substantial morbidity and frequent visits to health care professionals and may lead to amputation of a lower extremity.
2. Diabetic foot infections require attention to local (foot) and systemic (metabolic) issues and coordinated management, preferably by a multidisciplinary foot-care team (A-II) (table 1). The team managing these infections should include, or have ready access to, an infectious diseases specialist or a medical microbiologist (B-II).

Figure 1
Algorithm 1, part 1: approach to treating a diabetic patient with a foot wound


Figure 2
Algorithm 1, part 2: approach to treating a diabetic patient with a foot infection. 1Consider hospitalization if any of the following criteria are present: systemic toxicity (e.g., fever and leukocytosis); metabolic instability (e.g., severe hypoglycemia or acidosis); rapidly progressive or deep-tissue infection, substantial necrosis or gangrene, or presence of critical ischemia; requirement of urgent diagnostic or therapeutic interventions; and inability to care for self or inadequate home support. 


Figure 3
Algorithm 1, part 3: approach to assessing a diabetic patient with a foot infection who is not responding well to treatment. TcPO2, transcutaneous partial pressure of O2. 

Figure 4
Algorithm 2: approach to selecting antibiotic therapy for a diabetic patient with a foot infection. MRSA, methicillin-resistant Staphylococcus aureus. 


Figure 5
Algorithm 3: evaluating a diabetic patient who has suspected osteomyelitis of the foot. 1Cortical erosion, periosteal reaction, lucency and sclerosis, sequestrum, or involcrum. 2May be done percutaneously or operatively, preferably after antibiotic therapy has been stopped for 1–2 weeks (if safe to do so). 

Table 1
Infectious Diseases Society of America—United States Public Health Service Grading System for ranking recommendations in clinical guidelines. 


3. The major predisposing factor to these infections is foot ulceration, which is usually related to peripheral neuropathy. Peripheral vascular disease and various immunological disturbances play a secondary role.
4. Aerobic gram-positive cocci (especially Staphylococcus aureus) are the predominant pathogens in diabetic foot infections. Patients who have chronic wounds or who have recently received antibiotic therapy may also be infected with gram-negative rods, and those with foot ischemia or gangrene may have obligate anaerobic pathogens.
5. Wound infections must be diagnosed clinically on the basis of local (and occasionally systemic) signs and symptoms of inflammation. Laboratory (including microbiological) investigations are of limited use for diagnosing infection, except in cases of osteomyelitis (B-II).
6. Send appropriately obtained specimens for culture prior to starting empirical antibiotic therapy in all cases of infection, except perhaps those that are mild and previously untreated (B-III). Tissue specimens obtained by biopsy, ulcer curettage, or aspiration are preferable to wound swab specimens (A-I).
7. Imaging studies may help diagnose or better define deep, soft-tissue purulent collections and are usually needed to detect pathological findings in bone. Plain radiography may be adequate in many cases, but MRI (in preference to isotope scanning) is more sensitive and specific, especially for detection of soft-tissue lesions (A-I).
8. Infections should be categorized by their severity on the basis of readily assessable clinical and laboratory features (B-II). Most important among these are the specific tissues involved, the adequacy of arterial perfusion, and the presence of systemic toxicity or metabolic instability. Categorization helps determine the degree of risk to the patient and the limb and, thus, the urgency and venue of management.
9. Available evidence does not support treating clinically uninfected ulcers with antibiotic therapy (D-III). Antibiotic therapy is necessary for virtually all infected wounds, but it is often insufficient without appropriate wound care.
10. Select an empirical antibiotic regimen on the basis of the severity of the infection and the likely etiologic agent(s) (B-II). Therapy aimed solely at aerobic gram-positive cocci may be sufficient for mild-to-moderate infections in patients who have not recently received antibiotic therapy (A-II). Broad-spectrum empirical therapy is not routinely required but is indicated for severe infections, pending culture results and antibiotic susceptibility data (B-III). Take into consideration any recent antibiotic therapy and local antibiotic susceptibility data, especially the prevalence of methicillin-resistant S. aureus (MRSA) or other resistant organisms. Definitive therapy should be based on both the culture results and susceptibility data and the clinical response to the empirical regimen (C-III).
11. There is only limited evidence with which to make informed choices among the various topical, oral, and parenteral antibiotic agents. Virtually all severe and some moderate infections require parenteral therapy, at least initially (C-III). Highly bioavailable oral antibiotics can be used in most mild and in many moderate infections, including some cases of osteomyelitis (A-II). Topical therapy may be used for some mild superficial infections (B-I).
12. Continue antibiotic therapy until there is evidence that the infection has resolved but not necessarily until a wound has healed. Suggestions for the duration of antibiotic therapy are as follows: for mild infections, 1–2 weeks usually suffices, but some require an additional 1–2 weeks; for moderate and severe infections, usually 2–4 weeks is sufficient, depending on the structures involved, the adequacy of debridement, the type of soft-tissue wound cover, and wound vascularity (A-II); and for osteomyelitis, generally at least 4–6 weeks is required, but a shorter duration is sufficient if the entire infected bone is removed, and probably a longer duration is needed if infected bone remains (B-II).
13. If an infection in a clinically stable patient fails to respond to ⩾1 antibiotic courses, consider discontinuing all antimicrobials and, after a few days, obtaining optimal culture specimens (C-III).
14. Seek surgical consultation and, when needed, intervention for infections accompanied by a deep abscess, extensive bone or joint involvement, crepitus, substantial necrosis or gangrene, or necrotizing fasciitis (A-II). Evaluating the limb's arterial supply and revascularizing when indicated are particularly important. Surgeons with experience and interest in the field should be recruited by the foot-care team, if possible.
15. Providing optimal wound care, in addition to appropriate antibiotic treatment of the infection, is crucial for healing (A-I). This includes proper wound cleansing, debridement of any callus and necrotic tissue, and, especially, off-loading of pressure. There is insufficient evidence to recommend use of a specific wound dressing or any type of wound healing agents or products for infected foot wounds.
16. Patients with infected wounds require early and careful follow-up observation to ensure that the selected medical and surgical treatment regimens have been appropriate and effective (B-III).
17. Studies have not adequately defined the role of most adjunctive therapies for diabetic foot infections, but systematic reviews suggest that granulocyte colony-stimulating factors and systemic hyperbaric oxygen therapy may help prevent amputations (B-I). These treatments may be useful for severe infections or for those that have not adequately responded to therapy, despite correcting for all amenable local and systemic adverse factors.
18. Spread of infection to bone (osteitis or osteomyelitis) may be difficult to distinguish from noninfectious osteoarthropathy. Clinical examination and imaging tests may suffice, but bone biopsy is valuable for establishing the diagnosis of osteomyelitis, for defining the pathogenic organism(s), and for determining the antibiotic susceptibilities of such organisms (B-II).
19. Although this field has matured, further research is much needed. The committee especially recommends that adequately powered prospective studies be undertaken to elucidate and validate systems for classifying infection, diagnosing osteomyelitis, defining optimal antibiotic regimens in various situations, and clarifying the role of surgery in treating osteomyelitis (A-III).

Purpose of the guideline. Foot infections in persons with diabetes are a common, complex, and costly problem [1–4]. In addition to causing severe morbidities, they now account for the largest number of diabetes-related hospital bed—days [5] and are the most common proximate, nontraumatic cause of amputations [6, 7]. Diabetic foot infections require careful attention and coordinated management, preferably by a multidisciplinary foot-care team (A-II) [8–13]. The team managing these infections should preferably include, or have ready access to, an infectious diseases specialist or a medical microbiologist (B-III) [1]. Optimal management of diabetic foot infections can potentially reduce the incidence of infection-related morbidities, the need for and duration of hospitalization, and the incidence of major limb amputation [14, 15]. Unfortunately, these infections are frequently inadequately managed [16]. This may result from a lack of understanding of current diagnostic and therapeutic approaches, insufficient resources devoted to the problem, or a lack of effective multidisciplinary collaboration. The primary purpose of this guideline is to help reduce the medical morbidity, psychological distress, and financial costs associated with diabetic foot infections.
The focus of this guideline is primarily on managing the diabetic patient with suspected or evident foot infection, because other published guidelines cover the general management of the diabetic foot and diabetic foot ulceration [17–19]. The committee members realize that the realities of primary care practice and the scarcity of resources in some clinical situations will restrict the implementation of some of the recommended procedures and treatments. We believe, however, that in almost all settings, high-quality care is usually no more difficult to achieve or expensive than poor care and its consequences [20, 21].
This guideline should provide a framework for treating all diabetic patients who have a suspected foot infection. Some health care centers will be able to implement it immediately, whereas others will need increased resources, better staff training, and intensified coordination of available expertise. Use of this guideline may reduce the burdens (medical, financial, and ecological) associated with inappropriate practices, including those related to antibiotic prescribing, wound care, hospitalization decisions, diagnostic testing, surgical procedures, and adjunctive treatments. We hope it will contribute to reducing the rates of lower extremity amputation, in line with the international St. Vincent declaration [22]. Cost savings may ensue, although this may be offset by an increased demand for preventive foot care, diagnostic testing (especially MRI), and vascular interventions [12].
Methodology. This guideline committee is comprised of Infectious Diseases Society of America members with experience and interest in diabetic foot infections, many of whom also have experience in writing guidelines. Committee members are from several US states and other countries; their backgrounds represent academia, bench and clinical research, infectious diseases clinical practice, podiatry, and industry. Three of the members are also members of the International Working Group on the Diabetic Foot, which published its International Consensus Guidelines on Diagnosing and Treating Diabetic Foot Infections in 2003 [23]. After an extensive literature search (which included the MEDLINE database, the EBSCO database, the Cochrane Library, diabetic foot Web sites and bibliographies, and hand-searching of bibliographies of published articles), committee members reviewed and discussed all available evidence in a series of meetings and established consensus through discussion and debate over a period of 3 years. Three subcommittees drafted subsections that were modified and exchanged; these served as a basis for the final document, which underwent numerous revisions that were based on both internal and external reviews. Because of the relative paucity of randomized controlled trials or other high-quality evidence in this field, most of our recommendations are based on discussion and consensus (B-II) (table 1) [24]. Thus, we elected to offer a relatively brief summary and to provide an extensive bibliography for those who would like to review the data themselves.

Pathophysiology of Infection
A diabetic foot infection is most simply defined as any inframalleolar infection in a person with diabetes mellitus. These include paronychia, cellulitis, myositis, abscesses, necrotizing fasciitis, septic arthritis, tendonitis, and osteomyelitis. The most common and classical lesion, however, is the infected diabetic “mal perforans” foot ulcer. This wound results from a complex amalgam of risk factors [25, 26], which are summarized in table 2. Neuropathy plays the central role, with disturbances of sensory, motor, and autonomic functions leading to ulceration due to trauma or excessive pressure on a deformed foot that lacks protective sensation. Once the protective layer of skin is breached, underlying tissues are exposed to bacterial colonization. This wound may progress to become actively infected, and, by contiguous extension, the infection can involve deeper tissues. This sequence of events can be rapid (occurring over days or even hours), especially in an ischemic limb. Various poorly characterized immunologic disturbances, especially those that involve polymorphonuclear leukocytes, may affect some diabetic patients, and these likely increase the risk and severity of foot infections [27–30].
Table 2
Risk factors for foot ulceration and infection.


Aerobic gram-positive cocci are the predominant microorganisms that colonize and acutely infect breaks in the skin. S. aureus and the β-hemolytic streptococci (groups A, C, and G, but especially group B) are the most commonly isolated pathogens [31–38]. Chronic wounds develop a more complex colonizing flora, including enterococci, various Enterobacteriaceae, obligate anaerobes, Pseudomonas aeruginosa, and, sometimes, other nonfermentative gram-negative rods [39–43]. Hospitalization, surgical procedures, and, especially, prolonged or broad-spectrum antibiotic therapy may predispose patients to colonization and/or infection with antibiotic-resistant organisms (e.g., MRSA or vancomycin-resistant enterococci [VRE]) [44]. Although MRSA strains have previously been isolated mainly from hospitalized patients, community-associated cases are now becoming common [45] and are associated with worse outcomes in patients with diabetic foot infections [46–48]. Vancomycin (or glycopeptide)—intermediate S. aureus has been isolated in several countries. Of note, the first 2 reported cases of vancomycin-resistant S. aureus each involved a diabetic patient with a foot infection [49].
The impaired host defenses around necrotic soft tissue or bone may allow low-virulence colonizers, such as coagulase-negative staphylococci and Corynebacterium species (“diphtheroids”), to assume a pathogenic role [43, 50]. Acute infections in patients who have not recently received antimicrobials are often monomicrobial (almost always with an aerobic gram-positive coccus), whereas chronic infections are often polymicrobial [31, 36, 43, 51]. Cultures of specimens obtained from patients with such mixed infections generally yield 3–5 isolates, including gram-positive and gram-negative aerobes and anaerobes [14, 34, 37, 38, 40, 41, 52–58]. The pathogenic role of each isolate in a polymicrobial infection is often unclear. Table 3 lists common clinical infection syndromes and the pathogens most likely isolated in conjunction with them.

Table 3
Pathogens associated with various clinical foot-infection syndromes.

Evaluating The Patient, The Wound, and The Infection
Diabetic patients may develop many types of foot wounds, any of which can become infected. Infection should be diagnosed clinically on the basis of the presence of purulent secretions (pus) or at least 2 of the cardinal manifestations of inflammation (redness, warmth, swelling or induration, and pain or tenderness); not all ulcers are infected (figure 1) (B-II) [23]. Curing an infection often contributes to, but is not defined by, healing of an ulcer. Management of diabetic foot infections involves evaluating and determining the severity of infection as the basis for selecting the appropriate approach to treatment [15, 23, 40] (B-II). The issue of osteomyelitis is particularly complex and problematic and is thus dealt with separately.
Evaluation of the infection should occur at 3 levels, as outlined in tables 4 and 5 (B-III): the patient as a whole, the affected limb or foot, and the infected wound. The goal is to determine the clinical extent (table 4) and the microbial etiology (table 5) of the infection, the biology or pathogenesis of the wound, any contribution of altered foot biomechanics to the cause of the wound (and, thus, its ability to heal), any contribution of vascular (especially arterial) disease, and the presence of any systemic consequences of infection. Clinicians lacking the skills or experience to conduct any of these assessments should seek appropriate consultation.
Table 4
Evaluating the diabetic patient who has an infected foot.

Table 5
Collection of soft-tissue specimens from an infected diabetic foot for culture.


Determining The Severity of Infection
The results of the evaluations described in table 4 can be used to determine the overall severity of the infection and to formulate a management plan (figure 2) (B-II). Unfortunately, the lack of consensus on wound definitions and infection classification systems hampers comparison of published studies. The Wagner system [15, 40, 98, 99] has been widely used for 25 years but was developed for the “dysvascular” foot, is skewed toward severe disease, and contains all infections within a single grade [100–105]. Consensus is developing that the key issues in classifying a diabetic foot wound are its depth (in particular, which tissues are involved) and whether the wound is complicated by either ischemia or infection [23, 101, 106–108] (B-II). The International Consensus on the Diabetic Foot recently published a preliminary progress report on a diabetic foot ulcer classification system for research purposes [23]. The key elements are summarized by the acronym PEDIS (perfusion, extent/size, depth/tissue loss, infection, and sensation). The infection category includes grades 1 (no infection), 2 (involvement of skin and subcutaneous tissue only), 3 (extensive cellulitis or deeper infection), and 4 (presence of a systemic inflammatory response syndrome). Because this research-based system is designed to be applicable to all ulcers, it includes a category of grade 1 for uninfected lesions; grades 2–4 are similar to those we describe in table 6.
Table 6
Clinical classification of a diabetic foot infection.


For infected wounds (figure 2), the most important initial task is to recognize patients who require immediate hospitalization, parenteral and broad-spectrum empirical antibiotic therapy, and urgent consideration of diagnostic testing and surgical consultation. We have defined these potentially life-threatening infections as “severe.” Infections defined as “mild” must be distinguished from clinically uninfected lesions but are otherwise relatively easy to recognize. Defining infections as “moderate” poses the greatest difficulty, because this term covers a broad spectrum of wounds, some of which can be quite complicated and even limb threatening. Other classification schemes have used the terms “uncomplicated” and “complicated” synonymously with mild and moderate, but we wish to avoid confusion with the various complications that can beset a wound. The distinction between moderate and severe infections has less to do with the status of the foot than with the patient to whom it is attached. This distinction is complicated by the fact that ⩾50% of patients with a limb-threatening infection do not manifest systemic signs or symptoms. After debating several classification schemes, we propose the one presented in table 6 as a basis for subsequent discussions in and beyond this guideline (B-II).

Treatment of Infection
Avoid prescribing antibiotics for uninfected ulcerations. Some argue that many apparently uninfected diabetic foot ulcers are actually subclinically infected—that is, they contain a high “bioburden” of bacteria (usually defined as >105 organisms per gram of tissue) that results in “critical colonization” levels and impairs wound healing [54, 109–114]. Available published evidence does not support the use of antibiotics for the management of clinically uninfected ulcerations, either to enhance wound healing or as prophylaxis against infection [115, 116]. Because antibiotic use encourages antimicrobial resistance, incurs financial cost, and may cause drug-related adverse effects, we discourage therapy of uninfected ulcers. In some circumstances, it is difficult to decide whether a chronic wound is infected, such as when the foot is ischemic, has abnormal coloration or a fetid odor, has friable granulation tissue, is associated with unexpected pain or tenderness, or when an otherwise properly treated ulcer fails to show healing progress [117, 118]. In these unusual cases, a brief, culture-directed course of antibiotic therapy may be appropriate (C-III).
Determine the need for hospitalization. Hospitalization is the most expensive part of treating a diabetic foot infection, and deciding on its necessity requires consideration of both medical and social issues. Patients with infections that are either severe or complicated by critical limb ischemia should generally be hospitalized (C-III) [119, 120]. Some patients with apparently mild infections and more patients with moderate infections may also need hospitalization; this may be for observation, urgent diagnostic testing, or because complicating factors are likely to affect their wound care or adherence to antibiotic treatment. In the absence of these complicating features, most patients with mild or moderate infections can be treated as outpatients (A-II) [84, 121].
Stabilize the patient. Attending to the general metabolic state of the patient is essential [25, 122]. This may involve restoration of the fluid and electrolyte balances; correction of hyperglycemia, hyperosmolality, acidosis, and azotemia; and treatment of other exacerbating disorders. Critically ill patients who require surgery should usually be stabilized before transfer to the operating room, although surgery should usually not be delayed for >48 h after presentation to the hospital (B-III) [123]. The improvement of glycemic control may aid in both eradicating the infection and healing the wound [124]. As the infection improves, hyperglycemia may be easier to control.
Choose an antibiotic regimen. Selection of the antibiotic regimen initially involves decisions about the route of therapy, the spectrum of microorganisms to be covered, and the specific drugs to administer and later involves choosing the definitive regimen and the duration of treatment. Initial therapy is usually empirical and should be based on the severity of the infection and on any available microbiological data, such as recent culture results or current Gram-stained smear findings. For severe infections and for more-extensive, chronic moderate infections, it is safest to commence therapy with broad-spectrum agents. These should have activity against gram-positive cocci (including MRSA in locations where this pathogen is common), as well as gram-negative and obligate anaerobic organisms (B-III). To ensure adequate and prompt tissue concentrations, therapy should be given parenterally, at least initially (C-III). Although some suggest broad-spectrum empirical therapy for most infections [125–127], the majority of mild—and many moderate—infections can be treated with agents with a relatively narrow spectrum, such as those covering only aerobic gram-positive cocci (A-II) [84]. Although anaerobic organisms are isolated from many severe infections [42, 128], they are infrequent in mild-to-moderate infections [14, 84, 129], and there is little evidence to support the need for antianaerobic therapy in most infections (B-III). For mild-to-moderate infections in patients without gastrointestinal absorption problems and for whom an oral agent with the appropriate spectrum is available, oral therapy is often appropriate, especially with highly bioavailable agents (A-II). For mildly infected open wounds with minimal cellulitis, limited data support the use of topical antimicrobial therapy (B-I) [130].
Antibiotics vary in how well they achieve effective concentrations in infected diabetic foot lesions [131–137]; this is associated with the pharmacodynamic properties of the specific agent and, especially, the arterial supply to the foot, rather than with diabetes [138]. There are surprisingly few published clinical trials of antibiotic therapy for diabetic foot infection. Several antibiotic trials involving patients with various complicated skin and soft-tissue infections have included some patients with diabetic foot infections. Table 7 provides a list of published clinical trials that focused on therapy of diabetic foot infections, either exclusively or as an identified subset of a larger study. The lack of standardization among these trials makes the comparison of outcomes of different regimens inappropriate. The differing definitions of infection severity and clinical end points that were used in these publications highlight the need to develop a consensus classification system for future studies. On the basis of the available studies, no single drug or combination of agents appears to be superior to others [129].
Table 7
Antibiotic agents used in published clinical studies of diabetic foot infections.


Table 8 summarizes some potential empirical antibiotic regimens according to the clinical severity of the infection, although the available data do not allow us to recommend any specific antibiotic regimen for diabetic foot infections (B-II). These suggested agents are derived from available published clinical trials and our collective experience and are not meant to be inclusive of all potentially reasonable regimens. Similar agents could be used, depending on various clinical, microbiological, epidemiological, and financial considerations. Consider modifying antibiotic therapy when culture and susceptibility results are available (C-III). Empirical choices for patients who are not responding to antibiotic therapy should include agents that cover a different or more-extended spectrum of organisms (B-III) (figure 3). The regimens in table 8 are listed in approximate order of increasing broad-spectrum coverage; the order does not indicate preferences by the committee. Dosages of antibiotic agents should be selected according to suggestions of the US Food and Drug Administration, the drug's manufacturers, and the experience of the prescriber and should be modified on the basis of any relevant organ (especially renal) dysfunction and other clinical factors.
Table 8
Suggested empirical antibiotic regimens, based on clinical severity, for diabetic foot infections.


Determine the need for surgery. Many infections require surgical procedures that range from drainage and excision of infected and necrotic tissues to revascularization of the lower extremity and reconstruction of soft-tissue defects or mechanical misalignments [164–168]. Unfortunately, surgical treatment of diabetic foot infections is based on even less-structured evidence than that for antibiotic therapy [169]. Seek urgent surgical consultation for life- or limb-threatening infections, such as those presenting with necrotizing fasciitis, gas gangrene, extensive soft-tissue loss, or evidence of compartment syndrome, or those in limbs with critical ischemia (A-II) [170, 171]. A surgical specialist should also evaluate patients who have unexplained persistent foot pain or tenderness and/or evidence of a deep-space infection, deep abscesses, or progressive infection in the face of apparently appropriate medical care (figure 3). Timely and aggressive surgical debridement, including limited resections or amputations, may reduce the need for more-extensive amputation (B-II) [172, 173]. Pus under pressure, especially in an ischemic foot, can cause rapid and irreparable damage. For patients with less-serious infections, it may be appropriate to delay surgery to carefully observe the effectiveness of medical therapy or to determine the demarcation line between necrotic and viable tissue [174].
The surgeon must determine the adequacy of the blood supply to the remaining viable tissues, consider common operative pitfalls (e.g., infection spreading among foot compartments, to the deep plantar space, or along the tendon sheaths), and formulate a strategy for eventual soft-tissue cover (e.g., primary closure, delayed primary closure, secondary intention, or tissue transfer) [175–177]. The surgical approach should optimize the likelihood for healing and should attempt to preserve the integrity of the walking surface of the foot (B-II) [178]. In addition to manual dexterity, the surgeon must have sufficient knowledge and experience to judge when and how to intervene. The surgeon's training specialty is less important than his or her knowledge of the anatomy of the foot, the pathophysiology of ulceration and infection, and experience with and enthusiasm for the field [8]. In most instances, the surgeon should continue to observe the patient until the infection is under control and the wound is healing (B-III).
In some cases, amputation is the best or only option [170, 179]. Urgent amputation is usually required only when there is extensive necrosis or life-threatening infection [180]. Elective amputation may be considered for the patient who has recurrent ulceration (despite maximal preventive measures), has irreversible loss of foot function, or would require unacceptably prolonged or intensive hospital care [181, 182]. Selection of the level of amputation must take into consideration vascular, reconstructive, and rehabilitation issues [183, 184]. Generally, the surgeon should attempt to save as much of the limb as possible. However, a higher-level amputation that results in a more functional residual stump (even if a prosthesis is required) may be a better choice than preserving a foot that is mechanically unsound, unlikely to heal, or prone to future ulceration. When all or part of a foot has dry gangrene, it may be preferable (especially for a patient for whom surgery is a poor option) to let the necrotic portions autoamputate. It may also be best to leave adherent eschars in place, especially on the heel, until they soften enough to be more easily removed, provided there does not appear to be an underlying focus of infection [80, 81].
If the infected limb appears to be ischemic, the patient should be referred to a surgeon with vascular expertise [185]. In most cases, ischemia is due to larger-vessel atherosclerosis, rather than to “small-vessel disease” [68]. Because vessels above the knee and below the ankle tend to be relatively spared, lower-extremity atherosclerosis may be amenable to angioplasty or vascular bypass [186]. Patients with noncritical ischemia (e.g., those with an ankle to brachial artery blood pressure index of 0.5–0.9) can usually be successfully treated without a vascular procedure. For more-severe vascular disease of the foot, many centers have reported successful use of femoral-distal bypass procedures in diabetic patients [186–189]. For a patient with a severely infected ischemic foot, it is usually preferable to perform any needed revascularization early after recognizing the infection (i.e., within 1–2 days), rather than to delay this procedure in favor of prolonged (and potentially ineffective) antibiotic therapy (B-II) [123, 190]. On the other hand, careful debridement of necrotic infected material should not be delayed while awaiting revascularization. Optimal surgical management may require multiple, staged procedures [191].
Formulate a wound-care plan. The wound may require additional attention after the debridement performed during the initial assessment (table 4). The goal is to physically excise dead and unhealthy tissue, thereby enabling wound healing and removing a reservoir of potential pathogens [82, 192–194]. Any experienced clinician may perform limited debridement. This can usually be undertaken as a clinic or bedside procedure and without anesthesia, especially for a neuropathic foot. Sharp debridement with scalpel, scissors, or tissue nippers is generally preferable to hydrotherapy or topical debriding agents, which are less definitive and controllable and may require prolonged and repeated applications (B-III) [194, 195]. There are many wound-care products that are touted as being able to improve healing in various ways [17, 23, 196–199], but a discussion of these is beyond our scope. The infected wound should be dressed in a manner that allows daily inspection and encourages a moist wound-healing environment (B-III). No evidence favors any particular type of dressing; convenience and cost are important considerations. Removal of pressure from a foot wound (i.e., off-loading) is crucial to the healing process (A-I) [200, 201]. Many types of devices can off-load the infected wound, but it is important to choose one that permits easy inspection [202].
Adjunctive treatments. Investigators and industry representatives have advocated many types of wound-care treatments, including wound vacuum-drainage systems [203–206], recombinant growth factors [207–212], skin substitutes [203, 213–216], antimicrobial dressings [217–219], and maggot (sterile larvae) therapy [220–222]. Although each treatment likely has some appropriate indications, for infected wounds, available evidence is insufficient to recommend routine use of any of these modalities for treatment or prophylaxis.
Two adjunctive modalities do deserve brief comments. First, granulocyte colony-stimulating factors (G-CSFs) have now been investigated in 5 randomized trials involving diabetic foot infections [223–227]. A preliminary meta-analysis of these trials suggests that G-CSF does not accelerate resolution of infection but may significantly reduce the need for operative procedures (B-I) [228]. Second, several anecdotal and retrospective reports suggest that hyperbaric oxygen therapy may be of value for treatment of diabetic foot wounds, and a few recent prospective studies have shown promising results [229–232]. A recent Cochrane review concluded that hyperbaric oxygen therapy significantly reduced the risk of major amputation related to a diabetic foot ulcer [233] (B-I). Only additional randomized clinical trials can establish when, for whom, and with what protocols these expensive and limited resources might be used in the treatment of diabetic foot infections. Neither should be used as a substitute for proper surgical debridement and conventional therapy.

Careful observation of the patient's response to therapy (figure 4) is essential and should be performed daily for inpatients and perhaps every 2–5 days initially for outpatients (B-III). The primary indicators of improvement are resolution of local and systemic symptoms and clinical signs of inflammation. Blood test findings, including WBC counts [234, 235] and inflammatory markers, such as the erythrocyte sedimentation rate [122, 236, 237] and the C-reactive protein level [238], are of limited use for monitoring response, although is it reassuring to see elevated levels decrease and cause for concern when they do not.
When a hospitalized patient is ready for discharge or an outpatient returns for follow-up, the clinician should accomplish 4 tasks (figures 1, 2, and 4).
1. Select the definitive antibiotic regimen. Review the culture and drug susceptibility results and inquire about any adverse effects related to the current antibiotic therapy. Choose a definitive antibiotic regimen (including the treatment duration) on the basis of the results of cultures, imaging, or other investigations, and the initial clinical response (C-III). It is not always necessary to cover all microorganisms isolated from cultures. More virulent species (e.g., S. aureus and group A or B streptococci) should always be covered, but in a polymicrobial infection, less-virulent bacteria (e.g., coagulase-negative staphylococci and enterococci) may be less important (B-II). If the infection has not responded to the empirical regimen, select agents with activity against all isolates. For a clinically stable patient who has had ⩾1 unsuccessful courses of therapy, consider discontinuing antimicrobials for a few days and then collecting optimal specimens for culture (C-III).
2. Re-evaluate the wound. Inspect the site to ensure that the infection is responding and that the wound is healing. If neither is occurring, reassess the need for surgical intervention. No evidence supports giving antibiotics for the entire time that the wound remains open. Antibiotics should be used for a period defined by the biology of the infection and by the clinical syndrome, as suggested in table 9 (A-II). If clinical evidence of infection persists beyond the expected duration, check on the patient's compliance with antibiotics and re-evaluate for unaddressed adverse biological factors (figure 3). These may include the development of antibiotic resistance, a superinfection, an undiagnosed deep abscess or case of osteomyelitis, or ischemia that is more severe than was initially suspected.
Table 9
Suggested route, setting, and durations of antibiotic therapy, by clinical syndrome.


3. Review the off-loading and wound care regimens. Determine the effectiveness of, and the patient's compliance with, the prescribed regimens. Suggest (or seek consultation for) alternatives when necessary.
4. Evaluate glycemic control. Ensure that blood glucose levels and other aspects of the patient's metabolic status are adequately controlled.

Dealing with osteomyelitis is perhaps the most difficult and controversial aspect in the management of diabetic foot infections [239–244]. First among several problems is that the lack of a consensus definition of the disease hinders the comparison of available studies and experiences. Next, there are many available diagnostic tests, but they often yield equivocal results. Furthermore, the presence of osteomyelitis increases the likelihood of surgical intervention, including amputation, and the required duration of antibiotic therapy [240]. Finally, osteomyelitis impairs healing of the overlying wound and acts as a focus for recurrent infection.
When to consider the diagnosis. Consider osteomyelitis as a potential complication of any deep or extensive ulcer, especially one that is chronic or overlies a bony prominence (figure 5) [245]. Suspect underlying osteomyelitis when an ulcer does not heal after at least 6 weeks of appropriate care and off-loading. Any ulcer in which bone is either visible or can be easily palpated with a sterile blunt metal probe is likely to be complicated by osteomyelitis [83]. In patients with a limb-threatening infection, positive results of a probe-to-bone test may be taken as nearly sufficient for diagnosis, but the performance characteristics of this test have not yet been fully defined. A swollen foot in a patient with a history of foot ulceration, a “sausage toe” (i.e., a red, swollen digit) [246], or an unexplained high WBC count [235] or inflammatory markers [236] should also arouse suspicion of osteomyelitis (B-II). Finally, radiologically evident bone destruction beneath an ulcer should be considered to represent osteomyelitis unless proven otherwise [247].
Confirming the diagnosis. Because bony destruction is usually not seen on plain radiography performed during the early stages of disease and neuro-osteoarthropathy can mimic infection, diagnosing osteomyelitis at the time the patient first presents to the hospital can be difficult [248–250]. Characteristic progressive changes on serial plain radiographs may help in more-chronic cases [247, 251]. Radioisotope scans are more sensitive than radiographs for detecting osteomyelitis during the early stages of this diseases, but they are expensive and can be time-consuming [252]. The reported performance characteristics of various types of nuclear medicine scans varies, but the specificity of technetium bone scans is generally low [240, 253–255]. MRI is the most useful of the currently available imaging modalities (A-I) [90, 92, 94, 256–259]. MRI is the most accurate imaging study for defining bone infection, and it also provides the most reliable image of deep soft-tissue infections. The performance characteristics of all these diagnostic tests are highly correlated with the pretest probability of osteomyelitis, and they are most useful for intermediately probable cases [260]. The criterion (gold) standard for diagnosing osteomyelitis is isolation of bacteria from a reliably obtained sample of bone (using measures to minimize contamination) concomitant with histological findings of inflammatory cells and osteonecrosis (B-II). Unfortunately, few of the studies that have evaluated diagnostic tests or have assessed treatment outcomes have used this standard.
MRI is usually not needed as a first-line investigation in cases of diabetic foot infection. When osteomyelitis is a possibility, obtaining plain radiographs often suffices. If these radiographs show no evidence of pathological findings in bone, the patient should be treated for ∼2 weeks for the soft-tissue infection. If suspicion of osteomyelitis persists, perform plain radiography again 2–4 weeks later. If the initial films show classic changes suggestive of osteomyelitis (cortical erosion, periosteal reaction, and mixed lucency and sclerosis), and if there is little likelihood of a noninfectious osteoarthropathy, treat for presumptive osteomyelitis, preferably after obtaining appropriate specimens for culture (B-III). If findings of radiography are only consistent with, but not characteristic of, osteomyelitis, one of the following choices should be considered.
1. Additional imaging studies. MRI is the preferred imaging study, with nuclear medicine scans (that preferably use newer generation leukocyte [239, 261, 262] or immunoglobulin [263, 264] techniques) being a second choice. If results of the imaging tests are negative, osteomyelitis is unlikely; if results suggest osteomyelitis, consider whether bone biopsy is needed (vide infra).
2. Empirical treatment. Provide antibiotic therapy for another 2–4 weeks and then perform radiograph again to determine whether bony changes have progressed (which would suggest infection).
3. Bone biopsy. Use an appropriate procedure, as defined below. Collection of a sample of a bony lesion (either operatively or percutaneously) is recommended if the diagnosis remains in doubt after imaging or if osteomyelitis is likely but the etiologic agent or antibiotic susceptibilities are not predictable (B-II) [251, 265–268]. Some physicians would also obtain biopsy specimens of most mid- or hind-foot lesions, because these are more difficult to treat and more often lead to a high-level (i.e., above the ankle) amputation. Any properly trained physician (e.g., an orthopedic surgeon, podiatrist, interventional radiologist) can perform the biopsy. Percutaneous biopsy should preferably be done under fluoroscopic or CT guidance, traversing uninvolved skin if possible. For patients with sensory neuropathy, anesthesia may be unnecessary. Various types of bone-cutting needles, such as Jamshidi (Perfectum Corporation; distributed by Propper and Sons) and Ostycut (Bard Products; distributed by Angiomed) have been used. Obtain 2–3 specimens if possible, sending at least 1 for culture and another for histological analysis [269]. With small toe bones, it may only be possible to aspirate a few bony spicules. We found no published reports of complications of foot bone biopsy and consider it to be a safe procedure (B-II). Cultures of bone specimens provide more accurate microbiologic data than do those of soft-tissue specimens for patients with osteomyelitis [93, 268, 270].
Choosing between medical and surgical therapy. Traditionally, authorities have believed that resecting a bone with chronic osteomyelitis was essential for cure [240, 265]. Recently, some have disputed the routine need for surgical resection [239]. Definitive surgical solutions to osteomyelitis, such as ray and transmetatarsal amputations, may risk architectural reorganization of the foot, resulting in altered biomechanics and additional cycles of ulceration. Neuropathy and reduced systemic manifestations of infection may make osteomyelitis tolerable for the patient, who may thus opt for attempts at medical management. By contrast, these diabetic complications may also mask progressive bone destruction, with delayed or inadequate surgery resulting in poorly controlled infection, additional bone or soft-tissue necrosis, and a nonhealing wound.
These arguments have led some health care professionals to treat diabetic foot osteomyelitis with little or no surgical intervention [239]. Published reports on nonsurgical treatment with a prolonged (3–6 months) course of antibiotics have reported clinical success in ∼65%–80% of cases [155, 173, 237, 243, 271–276]. Unfortunately, these nonrandomized case series often fail to specify a definition of osteomyelitis, how patients were selected, whether patients were enrolled prospectively or even consecutively, and how much nonoperative debridement of bone was performed. The determination of which patients are suitable for nonsurgical treatment, as well as what duration of antibiotic therapy is needed, are important areas for future study. Meanwhile, there are 4 cases in which nonsurgical management of osteomyelitis might be considered (B-II).
1. There is no acceptable surgical target (i.e., radical cure of the infection would cause unacceptable loss of function).
2. The patient has ischemia caused by unreconstructable vascular disease but desires to avoid amputation.
3. Infection is confined to the forefoot, and there is minimal soft-tissue loss.
4. The patient and health care professional agree that surgical management carries excessive risk or is otherwise not appropriate or desirable.
When therapy for osteomyelitis fails, consider several issues. First, was the original diagnosis correct? Second, is there residual necrotic or infected bone or surgical hardware that should be resected or removed? Third, did the selected antibiotic regimen likely cover the causative organism(s) and achieve adequate levels in bone, and was it administered for a sufficient duration? Fourth, was the failure to eradicate bone infection the real cause of the current wound problem? Each case needs an individualized approach, usually in consultation with a knowledgeable surgeon. Selected patients may benefit from implanted antibiotics (e.g., embedded in beads or cement) [277–280], hyperbaric oxygen therapy, or revascularization, whereas others may elect long-term or intermittent antibiotic suppression or, in some cases, amputation.
Selecting an antibiotic regimen. The most appropriate duration of therapy for any type of diabetic foot infection has not been well defined [129]. It is important to consider the presence and amount of any residual dead or infected bone and the state of the soft tissues. When a radical resection leaves no remaining infected tissue, minimal antibiotic therapy is needed (B-II). Alternatively, if infected bone or soft tissue remain despite surgery, continued prolonged treatment is necessary. For osteomyelitis, some parenteral therapy may be beneficial, especially if an agent with suboptimal bioavailability is used (C-III). Parenteral therapy may be delivered in the outpatient setting, where available [153, 281, 282]. Our recommendations for duration of therapy are based on the clinical syndrome and are summarized in table 9.

The goals of treating a diabetic foot infection are the eradication of clinical evidence of infection and the avoidance of soft-tissue loss and amputations. Overall, expect a good clinical response (i.e., resolution of clinical evidence of infection) to appropriate therapy in 80%–90% of mild-to-moderate infections [84, 121, 130, 263] and in 60%–80% of severe infections or cases of osteomyelitis [130, 145, 147, 237, 283]. Factors associated with a poor outcome include signs of systemic infection [237], inadequate limb perfusion, osteomyelitis [273, 283–285], the presence of necrosis or gangrene [276], an inexperienced surgeon [286], and proximal location of the infection [287]. Relapses occur in ∼20%–30% of patients, especially in those with osteomyelitis; relapses may be difficult to differentiate from a reinfection. A recent survey of members of the Emerging Infections Network found that the acceptable median failure rate for treating diabetic foot osteomyelitis was 18% [288]. Conducting systematic audits of outcomes and patient treatment processes may be useful for individual practitioners and for multidisciplinary foot-care teams (B-II).

A patient who has had 1 foot infection is more likely to have another, making this a good time to reinforce preventive actions with the patient [11, 289, 290]. Detection of neuropathy before its complications ensue is the best method to prevent foot infections. Educate the patient about the importance of optimizing glycemic control, using appropriate footwear at all times, avoiding foot trauma, performing daily self-examination of the feet, and reporting any changes to health care professionals (A-II). Because basic screening can be completed in a few minutes, clinicians should reinforce these preventive measures by questioning patients about foot care and regularly examining their feet and shoes. Patients with severe neuropathy, substantial foot deformity, or critical ischemia should be referred to appropriate specialists to deal with these problems (A-II).

Recommended Research
Few of the recommendations in this guideline are based on properly designed and adequately powered randomized studies. There are 6 areas in which future research would be particularly helpful (A-III).
1. Establish a robust, validated, simple classification system for infected foot lesions to facilitate multicenter comparative studies of their natural history, diagnosis, and treatment. We support efforts to validate the International Consensus PEDIS system for foot-ulcer research purposes.
2. Determine whether there is a role for antibiotic therapy in managing clinically uninfected ulcers.
3. Determine optimal antibiotic regimens (agents, routes, and duration) for various types of soft-tissue and bone infections.
4. Establish a consensus definition of osteomyelitis in the diabetic foot.
5. Design and validate a simple, cost-effective algorithm for the diagnosis and treatment of infections, especially osteomyelitis.
6. Compare the outcomes of surgical and nonsurgical management of osteomyelitis.

Conflict of interest. B.A.L.: Advisory board membership, research support from, or speaker's bureau for Pfizer, Merck, Wyeth-Ayerst, Cubist, Vicuron, and Ortho-McNeil. A.R.B.: Speaker's bureau for Pfizer. H.G.D.: Speaker's bureau for GlaxoSmithKline and Pfizer, and research support from Theravance. J.M.E.: Advisory board membership, research support from, or speaker's bureau for AstraZeneca, Bayer, Bristol-Myers Squibb, Eli Lilly, Fujisawa, Janssen Ortho, and Pfizer. W.S.J.: Consultant and speaker's bureau for Pfizer and Merck. A.W.K.: Research support from Bayer, Pfizer, Merck, Ortho-McNeil, Cubist, Pharmacia, Vicuron, and Fujisawa and advisory board for Aventis, Pfizer, King Pharmaceuticals, Chiron, Vicuron, Cubist, and Bayer. C.N.: Former employee of Pfizer. J.S.T.: Research support from and speaker's bureau for Wyeth, Merck, Pfizer, Ortho-McNeil, Bayer, and Glaxo-SmithKline. J.L.L. and D.P.L.: No conflict.

•    a B.A.L. served as the chairman and A.R.B. served as the vice chairman of the Infectious Diseases Society of America Guidelines Committee on Diabetic Foot Infections.
•    b Deceased.
These guidelines were developed and issued on behalf of the Infectious Diseases Society of America.
Received July 2, 2004.
Accepted July 2, 2004.
© 2004 by the Infectious Diseases Society of America

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