2012 Infectious Diseases Society of America Clinical Practice Guideline for the Diagnosis, Guías, Proyectos, Investigaciones de Endocrinología

¡Descarga 2012 Infectious Diseases Society of America Clinical Practice Guideline for the Diagnosis y más Guías, Proyectos, Investigaciones en PDF de Endocrinología solo en Docsity! IDSA GUIDELIN 2012 Infectious Diseases Society of America Clinical Practice Guideline for the Diagnosis and Treatment of Diabetic Foot Infections* Benjamin A. Lipsky,' Anthony R. Berendt? Paul B. Cornia,* James C. Pile,* Edgar J. G. Peters? David G. Armstrong,* H. Gunner Deery' John M. Embil,* Warren S. Joseph? Adolf W. Karchmer,”” Michael S. Pinzur,'* and Eric Senneville”? "Department of Medicine, University of Washington, Veterans Affairs Puget Sound Health Care System, Seattle; "Bone Infection Unit, Nuffield Orthopaedic Centre, Oxtord University Hospitals NHS Trust, Oxtord; “Department of Medicine, University of Washington, Veteran Affairs Puget Sound Health Care System, Seattle; “Divisions of Hospital Medicine and Infectious Diseases, MetroHealth Medical Center, Cleveland, Ohio; “Department of Intemal Medicine, VU University Medical Center, Amsterdam, The Netherlands; “Southem Arizona Limb Salvage Alliance, Department of Surgery, University of Arizona, Tucson; "Northern Michigan Infectious Diseases, Petoskey: “Department of Medicine, University of Manitoba, Winnipeg, Canada; “Division of Podiatric Surgery, Department of Surgery, Roxborough Memorial Hospital, Philadelphia, Pennsylvania; "Department of Medicine, Division of Infectious Diseases, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts; * Department of Orthopaedic Surgery and Rehabilitation, Loyola University Medical Center, Maywood, Ilinois; and “Department of Infectious Diseases, Dron Hospital, Tourcoing, France Foot infections are a common and serious problem in persons with diabetes. Diabetic foot infections (DFIs) typically begin in a wound, most often a neuropathic ulceration. While all wounds are colonized with microorganisms, the presence of infection is defined by >2 classic findings of inflammation or purulence. Infections are then classified into mild (superficial and limited in size and depth), moderate (deeper or more extensive), or severe (accompanied by systemic signs or metabolic perturbations). This classification system, along with a vascular assessment, helps determine which patients should be hospitalized, which may require special imaging procedures or surgical interventions, and which will require amputation. Most DEIs are polymicrobial, with aerobic gram-positive cocci (GPC), and especially staphylococci, the most common causative organisms. Aerobic gram-negative bacilli are frequently copathogens in infections that are chronic or follow antibiotic treatment, and obligate anaerobes may be copathogens in ischemic or necrotic wounds. Wounds without evidence of soft tissue or bone infection do not require antibiotic therapy. For infected wounds, obtain a post-debridement specimen (preferably of tissue) for aerobic and anaerobic culture. Empiric antibiotic therapy can be narrowly targeted at GPC in many acutely infected patients, but those at risk for infection with antibiotic-resistant organisms or with chronic, previously treated, or severe infections usually require broader spectrum regimens. Imaging is helpful in most DFIs; plain radiographs may be sufficient, but magnetic resonance imaging is far more sensitive and specific. Osteomyelitis occurs in many diabetic patients with a foot wound and can be difficult to diagnose (optimally defined by bone culture and histology) and treat (often requiring surgical debridement or resection, and/or prolonged antibiotic therapy). Most DFIs require some surgical intervention, ranging from minor (debridement) to major (resection, amputation). Wounds must also be properly dressed and of£-loaded of pressure, and patients need regular follow-up. An ischemic foot may require revascularization, and some nonresponding patients may benefit from selected adjunctive measures. Employing multidisciplinary foot teams improves outcomes. Clinicians and healthcare organiz- ations should attempt to monitor, and thereby improve, their outcomes and processes in caring for DFls. Recelved 21 March 2012; accepted 22 March 2012. Correspondence: Benjamin A. Lipsky, MD, Uniersiyy of Washington, VA Puget ts important to realize that guidelines cannot always account for individual Sound Health Care System, 1660 S Columbian Way, Searle, WA 98108 variation among patients. They are not intended to supplant physician judgment —— (balipskyQuw.edul with respect to particular patients or special clinical situations. IDSA considers —— Clinical Infectious Diseases 201254/12):132-173 adherence to these guidelines to be voluntary, with the ultimate determination —— Published by Oxford University Press on behalf of the Infectious Diseases Society of regarding their application to be made by the physician in the light of each America2012. patient's individual cireumstances. DOL: 10:1093/cid/cis346 el32 » CID 2012:54 (15 June) e Lipsky et al 1ZOZ J9quiajdas gL uo jsanB Aq 696SSh/ZE19/Z1/+9/2/PN1e/p10/uo09dno"o1u peoe//:sdyy oy papeojumog EXECUTIVE SUMMARY Diabetic foot infections (DFIs) are a frequent clinical problem. Properly managed, most can be cured, but many patients needlessly undergo amputations because of improper diagnos- tic and therapeutic approaches. Infection in foot wounds should be defined clinically by the presence of inflammation or purulence, and then classified by severity. This approach helps clinicians make decisions about which patients to hospi- talize or to send for imaging procedures or for whom to rec- ommend surgical interventions. Many organisms, alone or in combinations, can cause DFÍ, but gram-positive cocci (GPC), especially staphylococci, are the most common. Although clinically uninfected wounds do not require anti- biotic therapy, infected wounds do. Empiric antibiotic regi- mens must be based on available clinical and epidemiologic data, but definitive therapy should be based on cultures of infected tissue. Imaging is especially helpful when seeking evidence of underlying osteomyelitis, which is often difficult to diagnose and treat. Surgical interventions of various types are often needed and proper wound care is important for successful cure of the infection and healing of the wound. Patients with a DFI should be evaluated for an ischemic foot, and employing multidisciplinary foot teams improves outcomes. Summarized below are the recommendations made in the new guidelines for diabetic foot infections. The expert panel followed a process used in the development of other Infectious Diseases Society of America (IDSA) guidelines, which in- cluded a systematic weighting of the strength of recommen- dation and quality of evidence using the GRADE (Grading of Recommendations Assessment, Development and Evaluation) system [1-6] (Table 1). A detailed description of the methods, background, and evidence summaries that support each of the recommendations can be found online in the full text of the guidelines. RECOMMENDATIONS FOR MANAGING DIABETIC FOOT INFECTIONS L In which diabetic patients with a foot wound should | suspect infection, and how should | classify it? Recommendations 1. Clinicians should consider the possibility of infection oc- curring in any foot wound in a patient with diabetes (strong, low). Evidence of infection generally includes classic signs of inflammation (redness, warmth, swelling, tenderness, or pain) or purulent secretions, but may also include additional or sec- ondary signs (eg, nonpurulent secretions, friable or discolored granulation tissue, undermining of wound edges, foul odor) (strong, low). 2. Clinicians should be aware of factors that increase the risk for DFI and especially consider infection when these factors are present; these include a wound for which the probe-to-bone (PTB) test is positive; an ulceration present for >30 days; a history of recurrent foot ulcers; a traumatic foot wound; the presence of peripheral vascular disease in the af- fected limb; a previous lower extremity amputation; loss of protective sensation; the presence of renal insufficiency; or a history of walking barefoot (strong, low). 3. Clinicians should select and routinely use a validated classification system, such as that developed by the International Working Group on the Diabetic Foot (IWGDF) (abbreviated with the acronym PEDIS) or IDSA (see below), to classify infec- tions and to help define the mix of types and severity of their cases and their outcomes (strong, high). The DEI Wound Score may provide additional quantitative discrimination for research purposes (weak, low). Other validated diabetic foot classification schemes have limited value for infection, as they describe only its presence or absence (moderate, low). 1. How should | assess a diabetic patient presenting with a foot infection? Recommendations 4. Clinicians should evaluate a diabetic patient presenting with a foot wound at 3 levels: the patient as a whole, the af- fected foot or limb, and the infected wound (strong, low). 5. Clinicians should diagnose infection based on the pres- ence of at least 2 classic symptoms or signs of inflammation (erythema, warmth, tenderness, pain, or induration) or puru- lent secretions. They should then document and classify the severity of the infection based on its extent and depth and the presence of any systemic findings of infection (strong, low). 6. We recommend assessing the affected limb and foot for arterial ischemia (strong, moderate), venous insufficiency, presence of protective sensation, and biomechanical problems (strong, low). 7. Clinicians should debride any wound that has necrotic tissue or surrounding callus; the required procedure may range from minor to extensive (strong, low). 111. When and from whom should | request a consultation for a patient with a diabetic foot infection? Recommendations 8. For both outpatients and inpatients with a DF, clini- cians should attempt to provide a well-coordinated approach by those with expertise in a variety of specialties, preferably by a multidisciplinary diabetic foot care team (strong, moderate). Where such a team is not yet available, the primary treating clinician should try to coordinate care among consulting specialists. IDSA Guideline for Diabetic Foot Infections e CID 2012:54 (15 June) + el33 1ZOZ J9quiajdas gL uo jsanB Aq 696SSh/ZE19/Z1/+9/2/PN1e/p10/uo09dno"o1u peoe//:sdyy oy papeojumog VII. When should | consider imaging studies to evaluate a diabetic foot infection, and which should | select? Recommendations 25. We recommend that all patients presenting with a new DEFI have plain radiographs of the affected foot to look for bony abnormalities (deformity, destruction) as well as for soft tissue gas and radio-opaque foreign bodies (strong, moderate). 26. We recommend using magnetic resonance imaging (MRI) as the study of choice for patients who require further (ie, more sensitive or specific) imaging, particularly when soft tissue abscess is suspected or the diagnosis of osteomyelitis remains uncertain (strong, moderate). 27. When MRI is unavailable or contraindicated, clinicians might consider the combination of a radionuclide bone scan and a labeled white blood cell scan as the best alternative (weak, low). VIll. How should | diagnose and treat osteomyelitis of the foot in a patient with diabetes? Recommendations 28. Clinicians should consider osteomyelitis as a potential complication of any infected, deep, or large foot ulcer, especially one that is chronic or overlies a bony prominence (strong, moderate). 29. We suggest doing a PTB test for any DF with an open wound. When properly conducted and interpreted, it can help to diagnose (when the likelihood is high) or exclude (when the likelihood is low) diabetic foot osteomyelitis (DFO) (strong, moderate). 30. We suggest obtaining plain radiographs of the foot, but they have relatively low sensitivity and specificity for confirm- ing or excluding osteomyelitis (weak, moderate). Clinicians might consider using serial plain radiographs to diagnose or monitor suspected DFO (weak, low). 31. For a diagnostic imaging test for DFO, we recommend using MRI (strong, moderate). However, MRI is not always necessary for diagnosing or managing DFO (strong, low). 32. If MRI is unavailable or contraindicated, clinicians might consider a leukocyte or antigranulocyte scan, preferably combined with a bone scan (weak, moderate). We do not rec- ommend any other type of nuclear medicine investigations (weak, moderate). 33. We suggest that the most definitive way to diagnose DFO is by the combined findings on bone culture and histology (strong, moderate). When bone is debrided to treat osteomyelitis, we suggest sending a sample for culture and histology (strong, low). 34. For patients not undergoing bone debridement, we suggest that clinicians consider obtaining a diagnostic bone biopsy when faced with specific circumstances, eg, diagnostic uncertainty, inadequate culture information, failure of response to empiric treatment (weak, low). 35. Clinicians can consider using either primarily surgical or primarily medical strategies for treating DFO in properly selected patients (weak, moderate). In noncompanative studies each ap- proach has successfully arrested infection in most patients. 36. When a radical resection leaves no remaining infected tissue, we suggest prescribing antibiotic therapy for only a short duration (2-5 days) (weak, low). When there is persist- ent infected or necrotic bone, we suggest prolonged (24 weeks) antibiotic treatment (weak, low). 37. For specifically treating DFO, we do not currently support using adjunctive treatments such as hyperbaric oxygen therapy, growth factors (including granulocyte colony- stimulating factor), maggots (larvae), or topical negative pressure therapy (eg, vacuum-assisted closure) (weak, low). IX. In which patients with a diabetic foot infection should | consider surgical intervention, and what type of procedure may be appropriate? Recommendations 38. We suggest that nonsurgical clinicians consider request- ing an assessment by a surgeon for patients with a moderate or severe DFI (weak, low). 39. We recommend urgent surgical intervention for most foot infections accompanied by gas in the deeper tissues, an abscess, or necrotizing fasciitis, and less urgent surgery for wounds with substantial nonviable tissue or extensive bone or joint involvement (strong, low). 40. We recommend involving a vascular surgeon early on to consider revascularization whenever ischemia complicates a DEFI, but especially in any patient with a critically ischemic limb (strong, moderate). 41. Although most qualified surgeons can perform an ur- gently needed debridement or drainage, we recommend that in DFI cases requiring more complex or reconstructive procedures, the surgeon should have experience with these problems and adequate knowledge of the anatomy of the foot (strong, low). X. What types of wound care techniques and dressings are appropriate for diabetic foot wounds? Recommendations 42. Diabetic patients with a foot wound should receive ap- propriate wound care, which usually consists of the following: a. Debridement, aimed at removing debris, eschar, and surrounding callus (strong, moderate). Sharp (or surgi- cal) methods are generally best (strong, low), but mech- anical, autolytic, or larval debridement techniques may be appropriate for some wounds (weak, low). b. Redistribution of pressure off the wound to the entire weight-bearing surface of the foot (“offloading”). el36 + CID 2012:54 (15 June) e Lipsky et al 1ZOZ J9quiajdas gL uo jsanB Aq 696SSh/ZE19/Z1/+9/2/PN1e/p10/uo09dno"o1u peoe//:sdyy oy papeojumog While particularly important for plantar wounds, this is also necessary to relieve pressure caused by dres- sings, footwear, or ambulation to any surface of the wound (strong, high). c. Selection of dressings that allow for moist wound healing and control excess exudation. The choice of dressing should be based on the size, depth, and nature of the ulcer (eg, dry, exudative, purulent) (strong, low). 43. We do not advocate using topical antimicrobials for treating most clinically uninfected wounds. 44. No adjunctive therapy has been proven to improve res- olution of infection, but for selected diabetic foot wounds that are slow to heal, clinicians might consider using bioengineered skin equivalents (weak, moderate), growth factors (weak, mod- erate), granulocyte colony-stimulating factors (weak, moder- ate), hyperbaric oxygen therapy (strong, moderate), or negative pressure wound therapy (weak, low). INTRODUCTION Foot infections in persons with diabetes are an increasingly common problem and are associated with potentially serious sequelae. The continued rise in incidence of diabetes in devel- oped, and to an even greater degree in many lesser-developed, countries, the increasing body weight of many diabetic patients, and their greater longevity all contribute to the growth of this problem. Diabetic foot infections (DFIs) usually arise either in a skin ulceration that occurs as a consequence of peripheral (sensory and motor) neuropathy or in a wound caused by some form of trauma. Various microorganisms in- evitably colonize the wound; in some patients 1 or more species of organisms proliferate in the wound, which may lead to tissue damage, followed by a host response accompanied by inflammation, that is, clinical infection. These infections can then spread contiguously, including into deeper tissues, often reaching bone. Even when DFIs are acute and relatively mild, they usually cause major morbidity, including physical and emotional distress and lost mobility, as well as substantial direct and indirect financial costs. Tf the infection progresses, many patients require hospitaliz- ation and, all too often, surgical resections or an amputation. Diabetic foot complications continue to be the main reason for diabetes-related hospitalization and lower extremity ampu- tations. The most recent data from the US Centers for Disease Control and Prevention (CDC) show that the annual number of hospitalizations for diabetic foot “ulcer/infection/inflam- mation” continued to rise steadily from 1980 to 2003, when it exceeded 111 000, thereby surpassing the number attributed to peripheral arterial disease (PAD) [7]. Not surprisingly, the annual number of hospital discharges for nontraumatic lower extremity amputations also increased steadily in the early 1990s, but fortunately have recently leveled off to 71000 in 2005 [8]. The additional good news is that the annual rate of amputations in the United States has almost halved in the past decade, to 4.6 per 1000 persons with diabetes, and most of this decrease has been in major (above the ankle) amputations [9]. These findings differ, however, from those in a more recent study from the United Kingdom, which found that between 1996 and 2005, while the number of amputations in patients with type 1 diabetes decreased substantially, in those with type 2 diabetes the number of minor amputations almost doubled and major amputations increased >40% [10]. Unfor- tunately, many diabetic patients who undergo a lower extre- mity amputation have a very poor quality of life and have a 5-year mortality rate similar to that of some of the most deadly cancers [11]. Since the publication of the initial DFI guidelines in 2004, we have learned a good deal about this complex problem. The Thomson Reuters ISI Web of Science for 2010 exemplifies the steadily increasing number of published reports on DFIs; the yearly number of published items rose from <than 20 in the 19905 to about 100 in the past few years (http://pcs. isiknowledge.com/). Two series of prospective observations from Europe exemplify the rigorous approach that is now be- ginning to provide the evidence we need to better manage DFIs. In 2010 the Observational Study of the Infected Diabetic Foot reported its findings on 291 evaluable consecutively en- rolled patients hospitalized with a DFI at any of 38 specialized hospital centers [12]. Among their findings were the following: almost all of the patients had peripheral neuropathy; more than half had PAD; and nearly half had evidence of osteomyel- itis. In the year prior to hospitalization, 40% had a history of an infected foot ulcer (perhaps implying inadequate outpatient care); most infections involved the toes (45%) or forefoot (34%) and were of moderate severity (by Infectious Diseases Society of America [IDSA] criteria). Clinicians performed cul- tures on 86% of patients (usually by swabbing the wound) and initiated antibiotic therapy for all patients (half of whom had received antibiotic therapy in the preceding 3 months) with a total of 62 combinations of agents. Highly noteworthy is that in 56% of patients the initial antibiotic regimen was changed, mainly because of a mismatch with the culture susceptibility results. The median duration of hospitalization was 3 weeks and 35% of patients underwent some type of lower extremity' amputation. Overall, 48% of patients had an unfavorable outcome of hospitalization. Worse, in follow-up a year after discharge, an additional 19% of patients had had an amputa- tion and 21% of the nonamputated patients had persistent or recurrent infection of the site, meaning that <30% of the en- rolled patients had a healed wound. The presence of PAD was IDSA Guideline for Diabetic Foot Infections e CID 2012:54 (15 June) + el37 1ZOZ J9quiajdas gL uo jsanB Aq 696SSh/ZE19/Z1/+9/2/PN1e/p10/uo09dno"o1u peoe//:sdyy oy papeojumog significantly associated with a poor outcome, yet it was often not addressed by the treating cli Another enlightening series of investigations conducted in ans. the past decade by the Eurodiale study group, a consortium of 14 centers of expertise in the field of diabetic foot disease, has greatly increased our knowledge on the epidemiology of this problem. During one year (2003-2004), 1229 consecutive patients presenting with a new foot ulcer, 27% of whom were hospitalized, were enrolled in an observational, prospective data collection study. At enrollment, more than one-quarter of the patients had been treated for >3 months before being re- ferred to a foot clinic and more than three-quarters had not had adequate wound ofFloading. Half of the patients had PAD and 58% of the foot ulcers were clinically infected; the one-third of patients with both neuropathy and PAD had more severe infections and underlying comorbidities [13]. After 1 year of follow-up, 23% of the patients had not healed their foot ulcer; among independent baseline predictors of nonhealing, PAD was key, and infection was a predictor only in patients with PAD [14]. Infection was also 1 of 4 indepen- dent predictors of minor amputation in these patients [15]. The highest costs per patient were those for hospitalization, antibiotic therapy, and surgery, and these increased with the severity of disease. The total cost per patient was >4 times higher for patients with infection and PAD than for those with neither [16]. Based on other recent studies and the collec- tive experience of the panel members, we believe that the following conclusions of the Eurodiale investigators apply to all parts of the world: treatment of many DFI patients is not in line with current guidelines; there are great variations in management among different countries and centers; currently available guidelines are too general, lacking spe- cific guidance; and, healthcare organizational barriers and personal beliefs result in underuse of recommended therapies 17]. Can we do better? Unquestionably. For >20 years, studies in many settings have reported improvements in outcomes with DFIs (especially reduced major amputation rates) when patients are cared for in specialty diabetic foot clinics or by specialized inpatient foot teams. A key factor in this success has been the multidisciplinary nature of the care. A decade ago Denmark established a multidisciplinary wound healing center and integrated diabetic foot care as an expert function in their national healthcare organization. They found that the center broadly enhanced the knowledge and understanding of wound problems, improved healing rates in patients with leg ulcers, and decreased rates of major amputations [18]. We agree with their conclusion that this model, with minor adjust- ments for local conditions, is applicable for most industrial- ized and developing countries. More recently, a report from one city in Germany showed a 37% reduction in the incidence of nontraumatic lower limb amputations (mostly in diabetic patients) when comparing data from 1990-1991 to those from 1994-2005, likely as a consequence of introducing a network of specialized physicians and defined clinical pathways for diabetic foot wound treatment and metabolic control [19]. One UK hospital reduced the total incidence of amputa- tions by 40% and major amputations by 62% over an 11-year period following improvements (including multidisciplinary team work) in foot care services [20]. They made the impor- tant observation that when they lost financial support for the multidisciplinary team the rates of amputation rose, but they fell again with renewed support. Recent studies have shown that adopting even relatively simple protocols with no increase in staffing can lead to improved outcomes and lower costs [21]. Hospitals in small or underdeveloped areas have also shown statistically significant improvements in outcomes of DFI after adopting systems of education and applying multidisciplinary protocols [22]. We agree with the con- clusions of the authors of a study that used a risk-based Markov analysis of data from Dutch studies that “manage- ment of the diabetic foot according to guideline-based care improves survival, reduces diabetic foot complications, and is cost-effective and even cost saving compared with standard care” [23]. Recently, the UK National Institute for Clinical Excellence (NICE) Guideline Development group published guidance for inpatient management of diabetic foot problems on the basis of a systematic review of published data [24]. We largely agree with their recommendations and offer this brief summary. Each hospital should have a care pathway for inpatients with a diabetic foot problem, including any break in the skin, inflam- mation, swelling, gangrene, or signs of infection. Optimally, a multidisciplinary foot care team comprised of professionals with the needed specialist skills should evaluate the patient's response to medical, surgical, and diabetes management within 24 hours of the initial examination. This evaluation will include determining the need for specialist wound care, debri- dement, pressure of-loading, or any other vascular or surgical interventions; reviewing the treatment of any infection (with antibiotic therapy based on guidelines established by each hospital); and assessing the need for interventions to prevent other foot deformities or recurrent foot problems [24]. The foot care team should also help to arrange discharge planning for both primary (and/or community) and specialist care. Another logical way of improving care would be to further empower those with most at stake—persons with diabetes. Although we know a good deal about how to prevent diabetic foot wounds [25], few studies have investigated the value of educating diabetic patients. In one prospective controlled el38 + CID 2012:54 (15 June) e Lipsky et al 1ZOZ J9quiajdas gL uo jsanB Aq 696SSh/ZE19/Z1/+9/2/PN1e/p10/uo09dno"o1u peoe//:sdyy oy papeojumog correlation of additional or secondary findings, for example, nonpurulent secretions, friable or discolored granulation tissue, undermining of the wound edges, or a foul odor, with evidence of infection [30]. However, none of these findings, either alone or in combination, correlate with a high colony count of bacteria in a wound biopsy [31]. Since the original IDSA DFI guidelines, we have advocated using the presence of >2 of the classic findings of inflammation to characterize a wound as infected. Although this definition is based only on expert consensus opinion, it has been used as the diagnostic criterion in many studies of DFÍ, including some used by the US Food and Drug Administration (FDA) to approve specific antibiotic agents for treating DFls. During the systematic review of the literature (see Introduc- tion) we found 177 studies that identified risk factors for devel- oping a foot infection in persons with diabetes. Identification of risk factors for DFI was the objective in only 2 studies [32, 33]. In one instance, factors that were significantly associated (by multivariate analysis) with developing a foot infection in- cluded having a wound that extended to bone (based on a posi- tive PTB test; odds ratio [OR], 6.7); a foot ulcer with a duration >30 days (OR, 4.7); a history of recurrent foot ulcers (OR, 2.4); a wound of traumatic etiology (OR, 2.4); or peripheral vascular disease, defined as absent peripheral arterial pulsations or an ankle-brachial index (ABI) of <0.9 (OR, 1.9) [32]. Among 199 episodes of DFI, only 1 infection occurred in a patient without a previous or concomitant foot ulcer. In the second study, a retrospective review of 112 patients with a severe DEL, multi- variate analysis identified 3 factors that were associated with developing a foot infection: a previous amputation (OR, 19.9); peripheral vascular disease, defined as any missing pedal pulsa- tion or an ABI of <0.8 (OR, 5.5); or loss of protective sensation (OR, 3.4). Psychological and economic factors did not contrib- ute significantly to infection [33]. Several other studies examined the association between a specific medical condition and various diabetic foot compli- cations, including infections. These types of studies lack a control group of patients without foot infection and are there- fore subject to selection bias. Some studies, each of which was retrospective and reported only a small number of cases, have suggested an association between renal failure and DFI [34- 36]. Finally, a report from Sri Lanka found that, compared to patients who wore shoes, those who walked barefoot for >10 hours per day had more web space and nail infections (14% vs 40%, respectively, P<.01) [37]. How to Classify Infection. In most published classifi- cation schemes, assessing infection is a subsection of a broader wound classification. These classification systems each have somewhat different purposes, and there is no consensus on which to use [38, 39]. Some classifications, including the Meggitt-Wagner [40] and SINBAD — (site, ischemia, neuropathy, bacterial infection, and death) [41], subjectively categorize infection only dichotomously, that is, as present or absent, and without clear definitions. We briefly summarize the key features of commonly used diabetic foot classification schemes and wound scoring systems. IWGDF (PEDIS) and IDSA. IWGDF developed a system for classifying diabetic foot wounds that uses the acronym PEDIS, which stands for perfusion, extent (size), depth (tissue loss), infection, sensation (neuropathy). While originally developed as a research tool [39], it offers a semiquantitative gradation for the severity of each of the categories. The infec- tion part of the classification differs only in small details from the classification developed by IDSA, and the 2 classifications are shown in Table 2. Major advantages of both classifications are clear definitions and a relatively small number of cat- egories, making them more user-friendly for clinicians having less experience with diabetic foot management. Importantly, the IDSA classification has been prospectively validated [13, 42, 43] as predicting the need for hospitalization (in one study, O for no infection, 4% for mild, 52% for moderate, and 89% for severe infection) and for limb amputation (3% for no in- fection, 3% for mild, 46% for moderate, and 70% for severe infection) [42]. Other Diabetic Foot Wound Classification Schemes. + Wagner—Wagner, in collaboration with Meggitt, devel- oped perhaps the first, and still among the most widely used, classification schemes for diabetic foot wounds [40, 44]. It assesses ulcer depth and the presence of infection and gangrene with grades ranging from 0 (pre- or postulcerative) to 5 (gangrene of the entire foot). The system only deals explicitly with infections of all types (deep wound abscess, joint sepsis, or osteomyelitis) in grade 3. + S(AD)/SAD—This is an acronym for 5 key points of foot ulcers: size, (area, depth), sepsis (infection), arterio- pathy, and denervation [45]. Each point has 4 grades, thus creating a semiquantative scale. Infection is graded as none, surface only, cellulitis, and osteomyelitis; these are not further defined. One study reported good inter- observer agreement [45]. Unlike the other key points, studies have not shown infection to be related to outcome of the foot ulcer [45, 46]. The SINBAD ulcer classification is a simplified version of the S(AD)/SAD system with a decreased number of grades of infection (present or absent) [41]. + University of Texas (UT) ulcer classification [47] —This system has a combined matrix of 4 grades (related to the depth of the wound) and 4 stages (related to the pres- ence or absence of infection or ischemia). The classifi- cation successfully predicted a correlation of the likelihood of complications in patients with higher IDSA Guideline for Diabetic Foot Infections e CID 2012:54 (15 June) + el41 1ZOZ J9quiajdas gL uo jsanB Aq 696SSh/ZE19/Z1/+9/2/PN1e/p10/uo09dno"o1u peoe//:sdyy oy papeojumog Table 2. Infectious Diseases Society of America and International Working Group on the Diabetic Foot Classifications of Diabetic Foot Infection IDSA Infection Clinical Manifestation of Infection PEDIS Grade Severity No symptoms or signs of infection 1 Uninfected Infection present, as defined by the presence of at least 2 of the following items Local swelling or induration Erythema Local tendemess or pain Local warmth Purulent discharge (thick, opaque to white or sanguineous secretion) Local infection involving only the skin and the subcutaneous tissue (without involvement of deeper 2 Mild tissues and without systemic signs as described below). If erythema, must be >0.5 cm to <2 cm around the ulcer. Exclude other causes of an inflammatory response of the skin (eg, trauma, gout, acute Charcot neuro-osteoarthropathy, fracture, thrombosis, venous stasis) Local infection (as described above) with erytherna > 2 cm, or involving structures deeper than skin 3 Moderate and subcutaneous tissues (eg, abscess, osteomyelitis, septic arthritis, fasciitis), and No systemic inflammatory response signs (as described below) Local infection (as described above) with the signs of SIRS, as manifested by 22 of the following: 4 Severe? Temperature >38"C or <36*C Heart rate >90 beats/min Respiratory rate >20 breaths/min or PACO, <32 mm Hg White blood cell count >12 000 or <4000 cells/uL or 210% immature (band) forms Abbreviations: IDSA, Infectious Diseases Society of America; PaCO,, partial pressure of arterial carbon dioxide; PEDIS, perfusion, extentísize, depth/tissue loss, infection, and sensation; SIRS, systemic inflammatory response syndrome. * Ischemia may increase the severity of any infection, and the presence of critical ischemia often makes the infection severe. Systemic infection may sometimes manifest with other clinical findings, such as hypotension, confusion, vomiting, or evidence of metabolic disturbances, such as acidosis, severe hyperglycemia, and new-onset azotemia [29, 43, 44]. stages and grades and a significantly higher amputation rate in wounds deeper than superficial ulcers [47]. A study in Brazil compared the UT and the S(AD)/SAD and SINBAD systems and found that all 3 predicted the outcomes of diabetic foot ulcers; the association of outcome with infection was stronger than that reported from the centers in Europe or North America [48]. Ulcer Severity Index [49] —This index measures 20 clini- cal parameters and allows determination of an infection score by combining the scores for erythema, edema, and purulence, while counting exposed bone separately. In 1 study, presence or absence of infection in this index was not associated with a difference in wound healing [49]. Diabetic Ulcer Severity Score (DUSS) and MAID [50, 51] —These scoring systems are based on specific wound characteristics associated with stages of wound repair. Studies have found no significant correlation between soft tissue infection and wound healing, although there was a trend toward more infection in the higher-risk groups [50, 51]. DFI Wound Score [52] —Lipsky et al developed this 10- item scoring system to measure outcomes in studies of various antimicrobial treatments for DFls (Table 3). The score consists of a semiquantitative assessment of the presence of signs of inflammation, combined with measurement of wound size and depth. Explicit defi- nitions allow numerical scoring of wound parameters. An evaluation of the wound score calculated for 371 patients with DEFI demonstrated that it significantly cor- related with the clinical response and that scores de- monstrated good internal consistency [52]. Patients with more severe wounds had higher scores; clinical response was favorable at the follow-up assessment in 94.8% with a baseline score <12 compared with 77.0% with a score >19, Surprisingly, excluding scores for wound discharge (purulent and nonpurulent), leaving an 8-item score, provided better measurement statistics [52]. The DFI Wound Score appears to be a useful tool for predicting clinical outcomes in treatment trials, but its complexity requires clinicians to use a scoring sheet [52]. Comparison of Classifications in the Literature. Each of these classifications may be used in clinical practice, but they have not been compared in a large prospective trial. The PEDIS, IDSA, UT, and S(AD)SAD classification systems are fairly simple to use and appear to help predict outcomes. The DFI and DUSS wound scores are relatively complex, but each has been validated in large research trials (Table 2) [52, 53]. el42 + CID 2012:54 (15 June) e Lipsky et al 1ZOZ J9quiajdas gL uo jsanB Aq 696SSh/ZE19/Z1/+9/2/PN1e/p10/uo09dno"o1u peoe//:sdyy oy papeojumog Table 3. Diabetic Foot Infection Wound Score (Items Compris- ing the Diabetic Foot Infection Wound Score Wound Parameters and Wound Measurements and the Method for Scoring Each) Item Assessment Scoring Wound parameters? Purulent discharge Absent 0 Present 3 Other signs and symptoms of inflammation? Absent 0 Nonpurulent discharge Mild 1 Erythema Moderate 2 Induration Tenderness Pain Severe 3 Local warmith Range of wound parameters (10-item) subtotal 021 Range of wound parameters (8-item) subtotal 0-15 Wound measurements* Size (crm?) <1 0 12 1 >25 3 >5-10 6 >1030 8 >30 10 Depth (mm) <5 0 5-9 3 10-20 7 >20 10 Undermining (mn) <2 3 2-5 5 >5 8 Range of wound measurements subtotal 3-28 Range of total 10-item? DFI wound score 3-49 Range of total 8-item? DFI wound score 3-43 The 10item score: purulent discharge, nonpurulent discharge, erythema, induration, tenderness, pain, warmth, size, depth, undermining. The 8item score leaves out purulent and nonpurulent secretions. Abbreviation: DF, diabetic foot infection. 2 Definitions for wound parameters and wound measurement can be found in the original article [52) B Each assessed and placed in one of the preassigned categories. 11. How should | assess a diabetic patient presenting with a foot infection? Recommendations 4. Clinicians should evaluate a diabetic patient presenting with a foot wound at 3 levels: the patient as a whole, the af- fected foot or limb, and the infected wound (strong, low). 5. Clinicians should diagnose infection based on the pres- ence of at least 2 classic symptoms or signs of inflammation (erythema, warmth, tenderness, pain, or induration) or puru- lent secretions. They should then document and classify the severity of the infection based on its extent and depth and the presence of any systemic findings of infection (strong, low). 6. We recommend assessing the affected limb and foot for arterial ischemia (strong, moderate), venous insufficiency, presence of protective sensation, and biomechanical problems (strong, low). 7. Clinicians should debride any wound that has necrotic tissue or surrounding callus; the required procedure may range from minor to extensive (strong, low). Evidence Summary The evaluation of a DFI should occur at 3 levels: first the patient as a whole, then the affected foot and limb, and finally the wound. The goal is to determine the extent of infection (local and systemic), its microbial etiology, the pathogenesis of the wound, and the presence of any contributing biomechani- cal, vascular, or neurological abnormalities [54]. Most DFls start in a skin ulceration [53]. Risk factors for these ulcers include complications of diabetes, for example, the presence of peripheral neuropathy (motor, sensory, or autonomic), per- ipheral vascular disease, neuro-osteoarthropathy, and impaired wound healing, as well as various patient comorbidities (eg, retinopathy or nephropathy) and maladaptive behaviors [53]. Diabetes also is associated with immunological perturbations, especially reduced polymorphonuclear leukocyte function, but also impaired humoral and cell-mediated immunity [55]. Importantly, local and systemic inflammatory responses to in- fection may be diminished in patients with peripheral neuro- pathy or arterial insufficiency. Because of the complex nature of DEI and the potential for rapid worsening (sometimes within hours), the clinician must assess the patient promptly, methodically, and repeatedly. The initial assessment should also include an evaluation of the patient's social situation and psychological state, which may influence his or her ability to comply with recommendations and appear to influence wound healing [43, 56, 57]. Systemic symptoms and signs of infection include fever, chills, delirium, diaphoresis, anorexia, hemodynamic instability (eg, tachycardia, hypotension), and metabolic derangements (eg, acidosis, dysglycemia, electrolyte abnormalities, worsening azotemia). Laboratory markers suggesting systemic infection include leukocytosis, a left-shifted leukocyte differential, and elevated inflammatory markers (eg, erythrocyte sedimentation rate [ESR], C-reactive protein [CRP]). An elevated level of procalcitonin has recently been found to be a useful adjunct to diagnosing various bacterial infections, including DFL. Two pro- spective studies [43, 57] of patients with a diabetic foot ulcer have shown that procalcitonin levels (using reported cutoff values of 17 mg/L and 0.08 ng/mL, respectively) correlate more accurately with clinical evidence of infection (using the IDSA criteria) than levels of white blood cells, ESR, or CRP. Levels of CRP and procalcitonin, especially when these values were com- bined, accurately distinguished clinically uninfected ulcers from those with mild or moderate infections [43]. We would welcome additional large studies of this biomarker in DFIs. IDSA Guideline for Diabetic Foot Infections e CID 2012:54 (15 June) + el43 1ZOZ J9quiajdas gL uo jsanB Aq 696SSh/ZE19/Z1/+9/2/PN1e/p10/uo09dno"o1u peoe//:sdyy oy papeojumog patients with a severe infection (as defined by the IDSA or IWGDF classification) require hospitalization, as these are often imminently limb-threatening and, in some cases, life- threatening. Conversely, the large majority of patients with a mild (IWGDF PEDIS grade 2) infection can be treated as out- patients, provided they are able to adhere to medical therapy and are closely followed to ensure they are improving and do not need urgent revascularization. Some individuals with a moderate (IWGDF PEDIS grade 3) infection may benefit from at least a brief course of inpatient treatment to more expedi- tiously obtain needed diagnostic studies and consultations and to i iate appropriate therapy. Outpatient therapy for a mod- erate infection is, however, often acceptable for reliable patients without critical ischemia, who do not have an urgent indication for surgical intervention [78, 79]. This includes many patients with osteomyelitis, which is usually a chronic infection that does not require urgent inpatient treatment (see question VII. Patients with deep foot infections often do not have fever, leukocytosis, or leftward shift in the white blood cell differen- tial or markedly elevated acute phase serum markers, but absence of these findings does not necessarily exclude a poten- tially serious infection. Worsened glycemic control is often the only systemic evidence of a serious infection in this setting [80-82]. Hospitalization is sometimes needed for patients who are unable to follow the necessary regimen for their foot infec- tion and who have no family or friends who can provide the needed support. For inpatients, prompt social work consul- tation, with particular attention to the patient's (or caregiver's) ability to comply with recommended wound care and off- loading, may help limit the duration of hospitalization and ensure the most appropriate discharge setting. No evidence-based admission or discharge criteria have been developed for patients with a DFL Although hospitaliz- ation is very expensive, a brief admission is often justified by the complexities of properly evaluating the patient, setting up a treatment regimen, and educating the patient and his/her caregivers. Consider discharge when all evidence of the sys- temic inflammatory response syndrome has resolved, the patient is metabolically stable, and any urgently needed surgery has been performed. Achieving adequate glycemic control is important, but this will usually require titration on an outpatient basis [83, 84]. The clinicians and patient should be clear on the antibiotic regimen (type, route, and duration of therapy), the wound care plans, and the ofFloading regimen, as well as the most appropriate site of care (eg, home, skilled nursing facility, outpatient infusion center). Patient and family preference will frequently play a role in these decisions, but the clinician must consider patient motiv- ation, expected adherence to therapy, availability of home support, and third-party payer issues [85]. Lastly, the patient should have appropriate outpatient follow-up appointments set up prior to discharge, and the hospital clinician should communicate with the patient's primary care provider and any consulting clinicians, as appropriate. V. When and how should | obtain specimen(s) for culture from a patient with a diabetic foot wound? Recommendations 16. For clinically uninfected wounds, we recommend not collecting a specimen for culture (strong, low). 17. For infected wounds, we recommend that clinicians send appropriately obtained specimens for culture prior to starting empiric antibiotic therapy, if possible. Cultures may be unnecessary for a mild infection in a patient who has not recently received antibiotic therapy (strong, low). 18. We recommend sending a specimen for culture that is from deep tissue, obtained by biopsy or curettage and after the wound has been cleansed and debrided. We suggest avoiding swab specimens, especially of inadequately debrided wounds, as they provide less accurate results (strong, moderate). Evidence Summary Because patients with clinically uninfected wounds rarely require antibiotic therapy, these wounds usually should not be cultured unless there is a reason to identify colonizing organ- isms for epidemiologic purposes. In patients with a clinically infected wound, however, properly obtained wound cultures provide highly useful information for guiding antibiotic therapy, particularly in those with chronic infections or who have recently been treated with antibiotics. One instance in which wound cultures may not be needed are mild infections in patients who have not recently received antibiotic therapy and who are at low risk for methicillin-resistant Staphylococ- cus aureus (MRSA) infection; these infections are predictably caused solely by staphylococci and streptococci. Isolation of antibiotic-resistant organisms, particularly MRSA [86-89], but also extended-spectrum P-lactamase (ESBL)-producing gram-negative bacilli and highly resistant Pseudomonas aeruginosa [90-94], is an increasing problem with DFI in most settings. Infection with these organisms re- quires specifically targeted antibiotic therapy, but empiric cov- erage in all cases is not prudent. Thus, where multidrug- resistant organisms are possible pathogens, it is essential to obtain optimal wound cultures prior to initiating antibiotic therapy. An approach to collecting specimens for culture is outlined in Table 5. Collect culture specimens only after the wound has been cleansed and debrided and prior to initiating antibiotic therapy. A sample obtained by curettage, the scraping of tissue from the ulcer base using a dermal curette or sterile scalpel blade, more accurately identifies pathogens than does rolling a el46 » CID 2012:54 (15 June) e Lipsky et al 1ZOZ J9quiajdas gL uo jsanB Aq 696SSh/ZE19/Z1/+9/2/PN1e/p10/uo09dno"o1u peoe//:sdyy oy papeojumog Table 5. Recommendations for Collection of Specimens for Culture From Diabetic Foot Wounds Do + Obtain an appropriate specimen for culture from almost all infected wounds + Cleanse and debride the wound before obtaining speciments) for culture + Obtain a tissue specimen for culture by scraping with a sterile scalpel or dermal curette (curettage) or biopsy from the base of a debrided ulcer + Aspirate any purulent secretions using a sterile needie and syringe + Promptly send specimens, in a sterile container or appropriate transport media, for aerobic and anaerobic culture (and Gram stain, if possible) Do not + Culture a clinically uninfected lesion, unless for specific epidemiological purposes + Obtain a specimen for culture without first cleansing or debriding the wound + Obtain a specimen for culture by swabbing the wound or wound drainage cotton swab over a wound. Although obtaining swab speci- mens is more convenient, they provide less accurate results, particularly if the wound has not been properly debrided. Swabs are often contaminated with normal skin flora or colo- nizers (thus giving false-positive cultures); they may also fail to yield deep-tissue pathogens and are less likely to grow anaerobic, and some fastidious aerobic, organisms (thus giving false-negative cultures) [95]. Furthermore, many clinical microbiology laboratories do not process swabs as rigorously as tissue specimens but merely report “mixed cutaneous flora” or “no S. aureus isolated.” A recent meta-analysis of studies examining the usefulness of superficial (compared with deeper) cultures in lower extremity wounds (half of which were in diabetic patients) found that their sensitivity was 49%, specificity 62%, positive likelihood ratio (LR) 1.1, and negative LR 0.67; thus, they provide minimal utility in altering pretest probabilities [96]. For clinicians who elect to use a swab for culture, some data support employing a semiquantitative tech- nique, like that described by Levine (rotating the swab over a 1-cm square area with sufficient pressure to express fluid from within the wound tissue) [97]. Other acceptable methods of culturing wounds include aspiration (with a sterile needle and syringe) of purulent secretions or perhaps cellulitic tissue, and tissue biopsy (usually obtained with a 4-6-mm punch device at the bedside or by resection at the time of surgery). Some microbiology laboratories can determine the quantitative count of organisms per gram of tissue, but this is rarely necessary for clinical situations [98]. Specimens must be placed in an appropriate sterile trans- port system and promptly delivered to the laboratory, where they should be processed for aerobic and anaerobic cultures. Given that culture results are generally not available for 2-3 days, a Gram-stained smear (if available) can provide immedi- ate information that may aid in initial antibiotic selection. When cultures yield multiple organisms, the Gram stain may also demonstrate which are predominant in the wound, thereby allowing tailored antibiotic therapy. Finally, the pres- ence of polymorphonuclear leukocytes on the Gram:stained smear suggests that infection is present (ie, the equivalent of purulent secretions). Recent studies have demonstrated that standard cultures identify only a small percentage of the microorganisms present in wounds, including DFls [99]. Molecular microbio- logical techniques can detect more organisms and provide the results considerably faster [100]. In addition, molecular tech- niques can detect the presence of pathogen virulence factors and genes encoding for antibiotic resistance [101]. Preliminary evidence suggests that having this information when a patient presents for treatment may aid the clinician in selecting optimal antibiotic regimens, resulting in improved outcomes. In one retrospective study of chronic wounds, complete healing occurred significantly more often after the implemen- tation of molecular diagnostics (298 of 479 [62.4%] vs 244 of 503 patients [48.5%)), the time to healing was significantly shorter (P<.05), and use of expensive “first-line” antibiotics declined in favor or targeted antibiotic therapy [102]. VI. How should | i ly select, and when should | modify, an antibiotic regimen for a diabetic foot infection? (See question Vil! for recommendations for al tic treatment of osteomyelitis) Recommendations 19. We recommend that clinically uninfected wounds not be treated with antibiotic therapy (strong, low). 20. We recommend prescribing antibiotic therapy for all infected wounds but caution that this is often insufficient unless combined with appropriate wound care (strong, low). 21. We recommend that clinicians select an empiric anti- biotic regimen on the basis of the severity of the infection and the likely etiologic agent(s) (strong, low). a. For mild to moderate infections in patients who have not recently received antibiotic treatment, we suggest that therapy just targeting aerobic gram-positive cocci (GPC) is sufficient (weak, low). b. For most severe infections, we recommend starting broad-spectrum empiric antibiotic therapy, pending culture results and antibiotic susceptibility data (strong, low). c. Empiric therapy directed at P. aeruginosa is usually unnecessary except for patients with risk factors for true infection with this organism (strong, low). IDSA Guideline for Diabetic Foot Infections e CID 2012:54 (15 June) + el47 1ZOZ J9quiajdas gL uo jsanB Aq 696SSh/ZE19/Z1/+9/2/PN1e/p10/uo09dno"o1u peoe//:sdyy oy papeojumog d. Consider providing empiric therapy directed against MRSA in a patient with a prior history of MRSA infec- tion; when the local prevalence of MRSA colonization or infection is high; or if the infection is clinically severe (weak, low). 22. We recommend that definitive therapy be based on the results of an appropriately obtained culture and sensitivity testing of a wound specimen as well as the patient's clinical response to the empiric regimen (strong, low). 23. We suggest basing the route of therapy largely on infec- tion severity. We prefer parenteral therapy for all severe, and some moderate, DFIs, at least initially (weak, low), with a switch to oral agents when the patient is systemically well and culture results are available. Clinicians can probably use highly bioavailable oral antibiotics alone in most mild, and in many moderate, infections and topical therapy for selected mild superficial infections (strong, moderate). 24. We suggest continuing antibiotic therapy until, but not beyond, resolution of findings of infection, but not through complete healing of the wound (weak, low). We suggest an initial antibiotic course for a soft tissue infection of about 1-2 weeks for mild infections and 2-3 weeks for moderate to severe infections (weak, low). Evidence Summary Avoidance of Prescribing Antibiotics for Clinically Unin- fected Wounds. is an important issue in treating diabetic foot infections. Table 6 provides an overview of the key elements in making this decision. Selecting an appropriate antibiotic regimen Table 6. Anti Should Consider Is there ical evidence of infection? Do not treat clinically uninfected wounds with antibiotics For clinically infected wounds consider the questions below: -1s there high risk of MRSA? Include antiMRSA therapy in empiric regimen if the risk is high (see Table 7) or the infection is severe -Has patient received antibiotics in the past month? If so, include agents active against gramunegative bacili in regimen If not, agents targeted against just aerobic gram-positive cocci may be sufficient -Are there risk factors for Pseudomonas infection?* If so, consider empiric antipseudomonal agent If not, empiric antipseudomonal treatment is rarely needed -What is the infection severity status? See Table 9 for suggested regimens for mild versus moderate/ severe infections Abbreviation: MRSA, methicillin-resistant Staphylococcus aureus. * Such as high local prevalence of Pseudomonas infection, warm climate, frequent exposure of the foot to water The limited available evidence does not support using anti- biotic therapy for treating clinically uninfected wounds, either to enhance healing or as prophylaxis against clinically overt infection [103, 104]. Furthermore, antibiotic use encourages antimicrobial resistance, incurs financial cost, and may cause drug-related adverse effects. Some wound specialists believe that diabetic foot wounds that lack clinical signs of infection may be “subclinically” infected—that is, they contain a high “bioburden” of bacteria (usually defined as >10% organisms per gram of tissue) that results in “critical colonization,” which might impair wound healing [105, 106]. Currently, there is little evidence to support this view. When it is difficult to decide whether a chronic wound is infected (eg, when the foot is ischemic and neuropathic), it may be appropriate to seek secondary signs of infection, such as abnormal coloration, a fetid odor, friable granulation tissue, undermining of the wound edges, an unexpected wound pain or tenderness, or failure to show healing progress despite proper treatment [31]. In these unusual cases, a brief, culture-directed course of anti- biotic therapy may be appropriate. Antibiotic Therapy of Clinically Infected Wounds. All clinically infected diabetic foot wounds require antibiotic therapy. Although this therapy is necessary, it is often insuffi- cient. Successfully treating a DFI also requires appropriate wound care (vide infra) [85]. Choosing an Antibiotic Regimen. The initial antibiotic regimen must usually be selected empirically, and it may be modified later on the basis of availability of additional clinical and microbiological information. Selecting an empiric regimen involves making decisions about the route of therapy, spectrum of microorganisms to be covered, and specific drugs to administer. These decisions should be revisited when decid- ing on the definitive regimen and the appropriate duration of treatment. Initial empiric therapy should be based on the severity of the infection and on any available microbiological data, such as recent culture results and the local prevalence of pathogens, especially antibiotic-resistant strains [107, 108]. The majority of mild, and many moderate, infections can be treated with agents that have a relatively narrow spectrum, usually covering only aerobic GPC [78]. In countries with warm climates, gram-negative isolates (especially P. aeruginosa) are more prevalent. Obligate anaerobic organisms are isolated from many chronic, previously treated, or severe infections [109-111]. Although they may be more common than pre- viously suspected [112, 113], they are not major pathogens in most mild to moderate infections [78, 113]. There is little evi- dence to support the need for antianaerobic antibiotic agents in most adequately debrided DFls. Treatment with oral anti- biotic agents (preferably ones with high bioavailability) is often appropriate for mild to moderate infections in patients el48 » CID 2012:54 (15 June) e Lipsky et al 1ZOZ J9quiajdas gL uo jsanB Aq 696SSh/ZE19/Z1/+9/2/PN1e/p10/uo09dno"o1u peoe//:sdyy oy papeojumog Table 8. Suggested Empiric Antibiotic Regimens Based on Clinical Severity for Diabetic Foot Infections* Infection Severity Probable Pathogen(s) Antibiotic Agent Comments Mild (usually treated Staphylococcus aureus with oral agentls)) (MSSA); Streptococcus spp Methicillin-resistant $S. aureus (MRSA) Moderate (may be MSSA; Streptococcus treated with oral or spp: initial parenteral Enterobacteriaceae; agentls]) or severe obligate anaerobes (usually treated with parenteral agentls)) MRSA Pseudomonas aeruginosa Dicloxacillin Clindamycin? Cephalexin' Levofloxacin” Amoxicillin-clavulanate? Doxycycline Trimethoprin/ sulfamethoxazole Levofloxacin” Cefoxitin? Ceftriaxone Ampicillin-sulbactam? Moxifloxacin” Ertapenem? Tigeoycline? Levofloxacin* or ciprofloxacin” with clindamycin? Imipenem-cilastatin” Linezolid? Daptomycin” Vancomycin' Piperacillin-tazobactam” Requires QID dosing: narrow- spectrum; inexpensive Usually active against community- associated MRSA, but check macrolide sensitivity and consider ordering a "D-est” before using for MRSA. Inhibits protein synthesis of some bacterial toxins Requires QID dosing; inexpensive Once-daily dosing; suboptimal against S. aureus Relatively broad-spectrum oral agent that includes anaerobic coverage Active against many MRSA 8: some gram-negatives; uncertain against streptococcus species Active against many MRSA 8: some gram-negatives; uncertain activity against streptococci Once-daily dosing; suboptimal against S. aureus Second-generation cephalosporin with anaerobic coverage Once-daily dosing, third-generation cephalosporin Adequate if low suspicion of P. aeruginosa Once-daily oral dosing. Relatively broad-spectrum, including most obligate anaerobic organisms Once-daily dosing. Relatively broad- spectrum including anaerobes, but not active against P. aeruginosa Active against MRSA. Spectrum may be excessively broad. High rates of nausea and vomiting and increased mortality waming. Nonequivalent to ertapenem + vancomycin in 1 randomized clinical trial Limited evidence supporting clindamycin for severe S. aureus infections; PO 84 1V formulations for both drugs Very broad-spectrum (but not against MRSA); use only when this is required. Consider when ESBL- producing pathogens suspected Expensive; increased risk of toxicities when used >2 wk Once-daily dosing. Requires serial monitoring of CPK Vancomycin MICs for MRSA are gradually increasing TID/QID dosing. Useful for broad- spectrum coverage. P. aeruginosa is an uncommon pathogen in diabetic foot infections except in special circumstances (2) IDSA Guideline for Diabetic Foot Infections e CID 2012:54 (15 June) + el51 1ZOZ J9quiajdas gL uo jsanB Aq 696SSh/ZE19/Z1/+9/2/PN1e/p10/uo09dno"o1u peoe//:sdyy oy papeojumog Table 8 continued. Infection Severity Probable Pathogen(s) Antibiotic Agent Comments MRSA, Enterobacteriacae, Pseudomonas, and obligate anaerobes Vancomycin* plus one of the following: ceftazidime, cefepime, piperacillin- tazobactam”, aztreonam,? or a carbapenem' Very broad-spectrum coverage; usually only used for empiric therapy of severe infection Consider addition of obligate anaerobe coverage if ceftazidime, cefepime, or aztreonam selected Agents in boldface type are those that have been most commonly used as comparators in clinical trials (see Table 7). The only agents currently specifically FDA- approved for diabetic foot infections are shown in itlics. Narrovespectrum agents (eg, vancomycin, linezolid, daptomycin) should be combined with other agents (eg, a fluoroquinolone) if a polymicrobial infection (especially moderate or severe) is suspected, Use an agent active against MRSA for patients who have a severe infection, evidence of infection or colonization with this organism elsewhere, or epidemiological risk factors for MRSA infection Select definitive regimens after considering the results of culture and susceptibility tests from wound specimens, as well as the clinical response to the empiric regimen. Similar agents of the same drug class can probably be substituted for suggested agents Some of these regimens do not have FDA approval for complicated skin and skin structure infections. Abbreviations: CPK, creatine phosphokinase; ESBL, extended-spectrum Blactamase; FDA, US Food and Drug Administration; IV, intravenous; MIC, minimum inhibitory concentration; MRSA, methicilin-resistant Staphylococcus aureus; MSSA, methicillin-sensitive Staphylococcus aureus; PO, oral; OID, 4 times a day; TID, 3 times a day. * Agents approved for treating skin and skin structure infections on the basis of studies that excluded patients with diabetic foot infections (eg, ceftaroline, telavancin) are not included. > Agents shown to be effective in clinical trials including patients with diabetic foot infections. * Daptomycin or linezolid may be substituted for vancomycin. countries), the drug's manufacturers, and their own experience; these may then need to be modified on the basis of any relevant organ (especially renal) dysfunction and other clinical factors. Duration of Therapy. Duration of antibiotic therapy for a DEFI should be based on the severity of the infection, the pres- ence or absence of bone infection, and clinical response to therapy (Table 8). Data from aforementioned clinical trials de- monstrate that most patients with just skin and soft tissue in- fections do well with 1-2 weeks of treatment. Routinely prescribing antibiotics for a fixed duration may result in an insufficient or, more often, unnecessarily prolonged course of therapy. This increases cost, potential for adverse drug-related events, and risk of development of antibiotic resistance. Anti- biotics can usually be discontinued once the clinical signs and symptoms of infection have resolved. There is no good evi- dence to support continuing antibiotic therapy until the wound is healed in order to either accelerate closure or prevent sub- sequent infection. VII. When should | consider imaging studies to evaluate a diabetic foot infection, and which should | select? Recommendations 25. We recommend that all patients presenting with a new DEFI have plain radiographs of the affected foot to look for bony abnormalities (deformity, destruction) as well as for soft tissue gas and radio-opaque foreign bodies (strong, moderate). 26. We recommend using magnetic resonance imaging (MRD as the study of choice for patients who require additional (ie, more sensitive or specific) imaging, particularly when soft tissue abscess is suspected or the diagnosis of osteo- myelitis remains uncertain (strong, moderate). 27. When MRI is unavailable or contraindicated, clinicians may consider the combination of a radionuclide bone scan and a labeled white blood cell scan as the best alternative (weak, low). Evidence Summary Imaging studies may help disclose or better define deep soft tissue purulent collections and are usually needed to detect pathological findings in bone. Plain radiographs may provide some information regarding the soft tissues in the patient with DEFI, for example, the presence of radio-opaque foreign bodies, calcified arteries, or soft tissue gas. They are primarily used, however, to determine whether there are bony abnormalities. In this regard, plain radiographs have only moderately helpful performance characteristics, with a recent meta-analysis re- porting pooled sensitivity of 0.54 and specificity of 0.68 for osteomyelitis [162]. They provide reasonably accurate infor- mation in the setting of established osteomyelitis [162-164]. Clinicians should consider radiologically evident bone destruc- tion beneath a soft tissue ulcer to represent osteomyelitis unless proven otherwise [163]. If the films show classic changes suggestive of osteomyelitis (cortical erosion, periosteal reaction, mixed lucency, and sclerosis), and if there is little likelihood of neuro-osteoarthropathy, it is reasonable to initiate treatment for presumptive osteomyelitis, preferably el52 + CID 2012:54 (15 June) e Lipsky et al 1ZOZ J9quiajdas gL uo jsanB Aq 696SSh/ZE19/Z1/+9/2/PN1e/p10/uo09dno"o1u peoe//:sdyy oy papeojumog after obtaining appropriate specimens for culture. The major limitation of sensitivity of plain films in the diagnosis of osteo- myelitis is the delayed appearance of cortical changes, with radiographic abnormalities lagging clinical disease by up to a month [165]. The continued absence of any bony abnormal- ities on repeat radiographs taken at least a few weeks apart probably excludes osteomyelitis. The major limitation of speci- ficity is differentiating infection from neuro-osteoarthropathy in a patient with bony destruction, especially if the patient has peripheral neuropathy. Among currently available imaging modalities, MRI provides the greatest accuracy (ie, combined sensitivity and specificity) for the detection of bone infection in the diabetic foot. One recent meta-analysis reported a pooled sensitivity of 90% and specificity of 79% for MRI in this setting [162], whereas a more inclusive meta-analysis calculated a specificity of 82.5% with a cut point of 90% sensitivity [166]. MRI also provides optimal definition of soft tissue infection, induding detecting sinus tracts, deep tissue ne- crosis, abscesses, and other inflammatory changes [162, 164, 166- 169]. Characteristic findings of diabetic foot osteomyelitis (DFO) on MRI include decreased signal intensity of affected bone on Tl-weighted images and increased intensity on T2-weighted and postcontrast images. It is not necessary to administer gadolinium to detect bony changes, but it increases the sensitivity for detec- tion of various soft tissue abnormalities [170]. MRI is also fre- quently useful to help determine the need for any type of surgical intervention [171]. MRI is usually not needed as a first-line inves- tigation in cases of DFI, and potential limitations may include limited availability (precluding or delaying the study), high cost, and a lack of a musculoskeletal radiologist skilled in interpreting MRls. Consider obtaining a MRI when there is suspicion of a deep abscess or when findings on plain radiography are equivocal for osteomyelitis. In this latter setting, no study has yet formally' compared serial plain films with MRI. MRI is usually not needed to diagnose osteomyelitis in a patient with observable or palpable bone and plain radiographs suggestive of osteomyelitis in that location [172]. When imaging beyond the capabilities of plain radiographs is needed but MRI is unavailable or contraindicated, a nuclear medicine scan is the best alternative. These scans have good sensitivity but (especially in the case of bone scans) relatively low specificity; almost any type of inflammatory condition will cause increased uptake, and the abnormalities are slow to resolve [161, 173]. Conventional bone scans (eg, %"Tc-MDP) have little value for either screening or anatomical reference [174]. Labeled leukocyte (with either %*Tc or In) or anti- granulocyte Fab fragment (eg, sulesomab) imaging [175] are the nuclear medicine procedures of choice for investigating a DEFI, with an overall accuracy of 80%-85% [174]. Combining the results of bone scanning with a labeled white blood cell scan appears to provide the best scanning accuracy but is laborious, expensive, and still less specific than MRI [176]. Although the results of one study suggested the benefit of ul- trasound for diagnosing deep soft tissue infection and perhaps osteomyelitis in the diabetic foot [177], there have been no further reports. Preliminary data suggest a possible role for combined fluorodeoxyglucose—positron emission tomography/ computed tomography (CT) (or MRD, although the utility and cost-effectiveness of this approach requires further study [178-180]. The same is true for using single-photon emission CT (SPECT)/CT with bone and leukocyte scanning [181]. Standard CT scanning is more sensitive than plain radiogra- phy (and in some cases MRI) in detecting cortical disruption, periosteal reaction, and sequestrae, but has relatively low specificity and plays a limited role in evaluating a DFI [182]. Distinguishing the bony changes of osteomyelitis from those of the less common entity of diabetic neuro-osteoarthro- pathy (Charcot foot) may be particularly challenging and re- quires considering clinical information in conjunction with imaging [183]. Clinical clues supporting neuro-osteoarthropa- thy in this context include midfoot location and absence of a soft tissue wound, whereas those favoring osteomyelitis include presence of an overlying ulcer (especially of the fore- foot or heel), either alone or superimposed on Charcot changes. Findings supporting neuro-osteoarthropathy on MRI are the presence of intra-articular bodies or subchondral cysts and involvement of multiple joints; findings favoring osteo- myelitis are diffuse signal enhancement involving an entire bone, replacement of fat adjacent to abnormal bone, and pres- ence of a sinus tract [169, 170, 184]. Consultation with an experienced musculoskeletal radiologist in distinguishing between these entities is invaluable [185]. VIII. How should | diagnose and treat osteomyelitis of the foot in a patient with diabetes? Recommendations 28. Clinicians should consider osteomyelitis as a potential complication of any infected, deep, or large foot ulcer, especially one that is chronic or overlies a bony prominence (strong, moderate). 29. We suggest doing a PTB test for any DFI with an open wound. When properly conducted and interpreted, it can help to diagnose (when the likelihood is high) or exclude (when the likelihood is low) DFO (strong, moderate). 30. We suggest obtaining plain radiographs of the foot, but they have relatively low sensitivity and specificity for confirm- ing or excluding osteomyelitis (weak, moderate). Clinicians might consider using serial plain radiographs to diagnose or monitor suspected DFO (weak, low). 31. For a diagnostic imaging test for DFO, we recommend using MRI (strong, moderate). However, MRI is not always necessary for diagnosing or managing DFO (strong, low). IDSA Guideline for Diabetic Foot Infections e CID 2012:54 (15 June) + el53 1ZOZ J9quiajdas gL uo jsanB Aq 696SSh/ZE19/Z1/+9/2/PN1e/p10/uo09dno"o1u peoe//:sdyy oy papeojumog these deficiencies, bone histology (when available) can be helpful. A study comparing culture to histopathology on 44 surgically obtained bone specimens from patients with DFO found that the 2 performed similarly [222]. Clinicians should take other available clinical, radiologic, and biologic par- ameters into account; a diagnostic scheme incorporating combinations of findings may prove useful for diagnosing DFO [185]. Imaging Studies. When considering osteomyelitis, we rec- ommend obtaining plain radiographs of the foot, as they are widely available and relatively inexpensive (see question VII). It may take weeks after the onset of bone disease for osteo- myelitis to become evident on plain radiographs [163, 177, 193]. Progressive changes seen on serial plain radiographs re- peated after 2-4 weeks may have greater sensitivity and speci- ficity [200]. Radioisotope scans are more sensitive than radiographs for detecting early osteomyelitis, but unfortu- nately they are rather nonspecific [223]. MRI is the most accu- rate imaging study for defining bone infection [166, 188, 224, 225], but accurately interpreting images requires a well-trained and experienced reader. MRT is not always needed to diagnose osteomyelitis (eg, when there is exposed grossly infected bone). The UK NICE guidelines [24] suggest that when osteo- myelitis is suspected but not confirmed by initial radiography, clinicians should use MRI or, if MRI is unavailable or contra- indicated, white blood cell scanning. The NICE guidelines offer receiver operating characteristic curves and Forrest plots relevant to the diagnosis of osteomyelitis. In preliminary studies, fluorodeoxyglucose positron emission tomography (or MRI) has better accuracy for confirming or excluding the di- agnosis of chronic osteomyelitis than plain MRI, but its role in diabetic patients is not yet established [225]. Management of Diabetic Patients With Osteomyelitis of the Foot. If MRI is unavailable, contraindicated, or otherwise difficult to justify, we think the following protocol should suffice: - If the plain radiograph has changes suggestive of osteo- myelitis (cortical erosion, active periosteal reaction, mixed lucency, and sclerosis), treat for presumptive osteomyel- itis, preferably after obtaining appropriate specimens for culture (consider obtaining bone biopsy, if available). - If the radiographs show no evidence of osteomyelitis, treat the patient with antibiotics for up to 2 weeks if there is soft tissue infection, in association with optimal care of the wound and ofFloading, Perform repeat radiographs of the foot 2-4 weeks after the initial radiographs. - If these repeat bone radiographs remain normal but sus- picion of osteomyelitis remains: + Where the depth of the wound is decreasing and the PTB test is negative, osteomyelitis is unlikely. + Where the wound is not improving or the PTB test is positive, 1 of the following choices should be considered: o Additional imaging studies, preferably MRL If results are negative, osteomyelitis is unlikely. + Bone biopsy for culture and histology. o Empiric treatment: Provide antibiotic therapy (based on any available culture results, and always covering at least for S. aureus) for another 2-4 weeks and then perform radiography again. Choosing Between Medical and Surgical Therapy. Bone resection has been considered essential for curing chronic osteomyelitis [186, 218], but this belief has been challenged by recent reports of cure with antibiotic therapy alone [165]. Definitive surgical solutions to osteomyelitis, such as ray and transmetatarsal amputations, may risk architectural reorganiz- ation of the foot, resulting in altered biomechanics and additional cycles of “transfer ulceration,” that is, skin break- down at a new high-pressure site. Neuropathy and attenuated systemic manifestations of infection may render osteomyelitis tolerable for the diabetic patient and may also mask progress- ive bone destruction. Delayed or inadequate surgery may impair control of infection and allow additional bone or soft tissue necrosis. No studies directly compare primarily surgical and primarily medical strategies, but nonsurgical treatment with a prolonged (3-6 months) course of antibiotics has a re- ported clinical success rate of 65%-80% [81, 189, 221, 226- 236]. Unfortunately, these data from nonrandomized case series often fail to specify a definition of osteomyelitis, how patients were selected, and how much nonoperative debride- ment of bone was performed. At the clinical extremes (ie, minimal or massive bone involvement), trained clinicians may find it easy to decide whether the patient requires surgical debridement of the infected bone or amputation. In the majority of cases, however, a didactic approach to manage- ment is not supported by strong evidence. There are 4 situations in which nonsurgical management of osteomyelitis might be considered [185, 189, 221, 234]: 1. There is no acceptable surgical target (ie, radical cure of the infection would cause unacceptable loss of function). 2. The patient has limb ischemia caused by unreconstruct- able vascular disease but wishes to avoid amputation. 3. Infection is confined to the forefoot, and there is minimal soft tissue loss. 4. The patient and healthcare professional agree that surgi- cal management carries excessive risk or is otherwise not ap- propriate or desirable. When therapy for osteomyelitis fails, clinicians should con- sider several possible reasons: el56 » CID 2012:54 (15 June) e Lipsky et al 1ZOZ J9quiajdas gL uo jsanB Aq 696SSh/ZE19/Z1/+9/2/PN1e/p10/uo09dno"o1u peoe//:sdyy oy papeojumog 1. Was the original diagnosis correct? 2. Is there residual necrotic or infected bone or surgical hardware that should be resected or removed? 3. Did the selected antibiotic regimen likely cover the cau- sative organism(s) and achieve adequate levels in bone, and was it administered for a sufficient duration? 4. Are noninfectious complications (eg, inadequate off- loading of the wound or insufficient blood supply to the foot), rather than failure to eradicate bone infection, the real problem? Each case needs an individualized approach (Table 10), pre- ferably in consultation with a multidisciplinary team. Selected patients may benefit from implanted antibiotic carriers (eg, A) [237-242], or from revascularization, whereas others may elect long-term or intermittent antibiotic suppression or, in some cases, amputation. There is no persuasive evidence that the use of adjunctive treatments, such as hyperbaric oxygen therapy, growth factors (including granulocyte colony- stimulating factor), maggots (larvae), or topical negative pressure therapy (eg, vacuum-assisted closure) are beneficial in the management of DFO [185]. Selecting an Antibiotic Regimen. A recent systematic review demonstrated the poor evidence base for making any recommendation on antibiotic therapy for DFO [185]. No data support the superiority of any specific antibiotic agent or treatment strategy, route, or duration of therapy. The results of one retrospective study of patients with DFO suggest that anti- biotic therapy directed by culture of bone (compared with empiric therapy) is associated with a significantly higher rate of resolution of the bone infection without surgery after a mean of 12 months” follow-up [221]. The most appropriate duration of therapy for any type of DFT is not well defined [149]. 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, only a short duration of antibiotic therapy is needed. Alternatively, if infected bone remains despite surgery, we advise prolonged treatment. For osteomyelitis, some initial parenteral antibiotic therapy may be beneficial, especially if an agent with suboptimal bioavail- ability is selected, but predominantly oral therapy with a highly bioavailable agent is probably adequate. Parenteral therapy may be delivered in the outpatient setting, where this service is available [241, 243, 244]. Recommendations for dur- ation of therapy are based on the clinical syndrome and are summarized in Table 11. Although there are no tests that have been proven to correlate with long-term resolution of osteo- myelitis, the consensus of the panel is that the following are suggestive of a response: a decrease in previously elevated Table 10. Approach to Treating a Patient With Diabetic Foot Osteomyelitis When to consider a trial of nonsurgical treatment + No persisting sepsis (after 48-72 h if on treatment) + Patient can receive and tolerate appropriate antibiotic therapy + Degree of bony destruction has not caused irretrievable compromise to mechanics of foot (bearing in mind potential for bony reconstitution) + Patient prefers to avoid surgery + Patient comorbidities confer high risk to surgery + No contraindications to prolonged antibiotic therapy (eg, high risk for C. difficile infection) + Surgery not otherwise required to deal with adjacent soft tissue infection or necrosis When to consider bone resection + Persistent sepsis syndrome with no other explanation + - Inability to deliver or patient to tolerate appropriate antibiotic therapy + Progressive bony deterioration despite appropriate therapy + Degree of bony destruction irretrievably compromises mechanics of foot + Patient prefers to avoid prolonged antibiotics or to hasten wound healing + Toachieve a manageable soft tissue wound or primary closure + Prolonged antibiotic therapy is relatively contraindicated or is not likely to be effective (eg, presence of renal failure) inflammatory markers (especially the ESR); resolution of any overlying soft tissue infection; healing of any wound; and evol- ution of radiographic changes that suggest healing. IX. In which patients with a diabetic foot infection should | consider surgical intervention, and what type of procedure may be appropriate? Recommendations 38. We suggest that nonsurgical clinicians consider request- ing assessment by a surgeon for patients with a moderate or severe DFI (weak, low). 39. We recommend urgent surgical intervention for most foot infections accompanied by gas in the deeper tissues, an abscess, or necrotizing fasciitis, and less urgent surgery for wounds with substantial nonviable tissue or extensive bone or joint involvement (strong, low). 40. We recommend involving a vascular surgeon early on to consider revascularization whenever ischemia complicates a DEFI, but especially in any patient with a critically ischemic limb (strong, moderate). 41. Although most qualified surgeons can perform an ur- gently needed debridement or drainage, we recommend that in DFI cases requiring more complex or reconstructive pro- cedures, the surgeon should have experience with these problem and adequate knowledge of the anatomy of the foot (strong, low). IDSA Guideline for Diabetic Foot Infections e CID 2012:54 (15 June) + el57 1ZOZ J9quiajdas gL uo jsanB Aq 696SSh/ZE19/Z1/+9/2/PN1e/p10/uo09dno"o1u peoe//:sdyy oy papeojumog Table 11. Suggested Route, Setting, and Duration of Ar Therapy, by Clinical Syndrome Table 12. Signs of a Possibly Imminently Limb-Threatening Infection Site of Infection, by Route of Duration of Severity or Extent Administration Setting Therapy Softtissue only Mild Topical or oral Outpatient — 1-2wk; may extend Up to4 wk if slow to resolve Moderate Oral (or initial Outpatient/ 1-3 wk parenteral) inpatient Severe Initial Inpatient, 24 wk parenteral, then switch to outpatient oral when possible Bone or joint No residual Parenteral or... 25d infected tissue (eg, oral postamputation) Residual infected Parenteral or 13 wk soft tissue (but oral not bone) Residual infected Initial 46 wk (but viable) bone parenteral, then consider oral switch No surgery, or Initial >3 mo residual dead bone parenteral, postoperatively then consider oral switch Evidence Summary Determining the Need for Surgery. Many infections require surgical procedures, ranging from minor (eg, drainage and ex- cision of infected and necrotic tissues) to major (eg, recon- struction of soft tissue or bony defects, revascularization of the lower extremity, and lower limb amputation) [245-249]. Clin- icians should seek urgent surgical consultation for patients presenting with clinical evidence of a life- or limb-threatening infection (Table 12), or if the involved limb is critically is- chemic (Table 4) [250, 251]. A surgical specialist should also evaluate any patient who has unexplained persistent foot pain or tenderness or evidence of a deep-space infection or abscess. The absence of fever or leukocytosis should not dissuade the clinician from considering surgical exploration of a DFI [252, 253]. The most common site for a severe foot infection is the plantar surface. A plantar wound accompanied by dorsal erythema or fluctuance suggests that the infection has passed through fascial compartments, likely requiring surgical + Evidence of systemic inflammatory response + Rapid progression of infection e Extensive necrosis or gangrene + Crepitus on examination or tissue gas on imaging + Extensive ecchymoses or petechias + Bullae, especially hemorrhagic + New onsetwound anesthesia + Pain outof proportion to clinical findings + Recent loss of neurologic function + Critical limb ischemia + Extensive soft tissue loss + Extensive bony destruction, especially midfoothindfoot + Failure of infection to improve with appropriate therapy In clinical settings with less advanced healthcare available, lesser degrees of infection severity may make an infection limb-threatening. drainage (Figure 1). Prompt and adequate surgical debride- ment, including limited resections or amputations, may de- crease the likelihood that a more extensive amputation is needed [227, 254]. The progressive development of an abscess within the foot, especially in the presence of ischemia, can rapidly lead to irreparable tissue damage. Various publications suggest that there are between 4 and 7 compartments in the foot; the 4 in the plantar aspect are medial, lateral, and central plantar and deep plantar (Figure 1) [255, 256]. The key element of any surgical approach is to reach the appropriate foot compartment(s) and extend the ex- ploration and debridement to healthy tissue [257]. Appropri- ate planning, careful tissue dissection, [257] and using longitudinal skin incisions respecting the specific compart- ments can lead to a durable, weight-bearing, and often non- painful plantar surface [255]. An example of a well-tolerated plantar incision is one that begins posterior to the medial mal- leolus and extends laterally and distally toward the midline, then distally to end between the metatarsal heads. This incision can be modified to end medially or laterally, depend- ing on the involved compartments or anatomic location of the infection. If required, this incision can also be modified to include a partial ray (metatarsal) amputation or extended more proximally to resect all toes (transmetatarsal amputa- tion) or to undertake a midfoot/rearfoot amputation. For patients with an early, evolving infection, it may be best to delay surgery in an attempt to avoid the consequent scar- ring and deformity. In those with a nonsevere infection, care- fully observing the effectiveness of medical therapy and the demarcation line between necrotic and viable tissue before op- erating may be prudent [255, 258]. If clinical findings worsen, surgical intervention is usually needed. The surgeon must el58 » CID 2012:54 (15 June) e Lipsky et al 1ZOZ J9quiajdas gL uo jsanB Aq 696SSh/ZE19/Z1/+9/2/PN1e/p10/uo09dno"o1u peoe//:sdyy oy papeojumog We generally prefer sharp debridement (with scalpel, scis- sors, or tissue nippers) to other techniques that are less defini- tive and controlable and may require prolonged and repeated applications [301, 302]. Although sharp debridement has been proven to be efficacious in clinical trials [278, 303], a systema- tic review found little strong evidence of the effectiveness of either sharp debridement or topical debriding agents [283]. Debridement should be repeated as often as needed if nonvi- able tissue continues to form [304]. Other methods of debride- ment include autolytic dressings and biological debridement with maggots (ie, larvae of Lucilia sericata [green-bottle fly]). The exact mechanism of maggot biotherapy is not yet known, but it appears to be useful for carefully selected necrotic and infected wounds [305-308]. Limited evidence supports the use of hydrosurgery systems, an emerging technology that simul- taneously cuts and aspirates soft tissue, but they are relatively expensive [309, 310]. Following debridement, measure and record the wound size, the extent of any surrounding cellulitis, and the quality and quantity of any drainage (including color, lucency, and odor); taking photographs is helpful in this regard. Bear in mind when documenting treatment that >1 clinician will treat most patients during the healing process. Off-loading Pressure. Relieving pressure from a diabetic foot wound (offloading) is a vital part of wound care [311]. The choice of off-loading modality should be based on the wound's location, the presence of any associated PAD, the presence and severity of infection, and the physical character- istics of the patient and their psychological and social situ- ation. The total contact cast, often considered the “gold standard” device, redistributes pressure to the entire weight- bearing surface to accelerate healing of a neuropathic ulcer [299, 312, 313]. Its main advantage may be that it is irremova- ble, leading to the development of other devices, such as the instant total contact cast [314], that are easier to apply, less expensive, and equally efficacious. The total contact cast should only be used with caution in patients with severe PAD or active infection, as it precludes viewing the wound [315]. There are many types of removable off loading devices from which to choose [316-318], but patients often remove them, especially when they are at home. Studies over the past 2 decades have established that the majority of diabetic foot ulcers take at least 20 weeks to heal [519, 320]. If a diabetic foot wound fails to heal despite good wound care, the clinician should initiate a reevaluation of management (Table 13). This should include ensuring that perfusion of the limb is adequate and that any infection (especially osteomyelitis) has been adequately addressed. Con- sider obtaining a biopsy of a recalcitrant or atypical wound, as a lesion that appears to be a diabetic foot ulcer may on occasion be a malignancy (eg, a melanoma or Kaposi sarcoma). After addressing these issues, the clinician should Table 13. Questions to Ask When Dealing With Nonresponse or Recurrence Is there a failure of wound healing? + Is the patient adhering to the wound care regimen? + Has the wound been adequately debrided? + Has the wound been appropriately dressed? + Has the wound been adequately ofkloaded? + Is there unidentified or untreated ischemnia? + Isthe lesion malignant? + Is there undiagnosed or improperly treated infection? Is there a failure of infection to respond? + Is there unidentified or untreated limb ischernia? + _ Is there unidentified necrotic soft tissue or bone? + Isthere an undrained abscess? + Has the wound been adequately debrided? +. Is there osteomyelitis that has not yet responded? + Isthere an untreated oran unidentified pathogen? + Isthere an antibiotic delivery problem? + Isthere an antibiotic nonadherence issue? + Have all metabolic aberrations been corrected? consider using adjunctive treatments to promote wound healing. None of these measures, however, have been shown to improve resolution of infection; moreover, they are expens- ive, not universally available, and may require consultation with experts, and the reports supporting their utility are mostly flawed. + Hyperbaric oxygen therapy: A limited number of ran- domized controlled trials are available to support its use for wound healing (but not resolving infection) [321- 324]. + Platelet-derived growth factors: Although an initial study demonstrated benefit, subsequent investigations have not shown these treatments to improve healing, or they have been conducted in a fashion where the data cannot be in- terpreted in the context of routine care [287, 325, 326]. + Granulocyte colony-stimulating factor (G-CSF): Based on results of 5 randomized clinical trials using various prep- arations and protocols, adding G-CSF did not signifi- cantly affect the likelihood of resolution of infection or wound healing but was associated with a significantly reduced likelihood of lower extremity surgical interven- tions (including amputation) and reduced duration of hospital stay, but not duration of systemic antibiotic therapy. The available data are not sufficiently robust to support the routine use of this therapy [327-333]. + Bioengineered skin equivalents: The data supporting the effectiveness of these products are not of sufficient quality or robustness to support their use [334-336]. IDSA Guideline for Diabetic Foot Infections e CID 2012:54 (15 June) + el6l 1ZOZ J9quiajdas gL uo jsanB Aq 696SSh/ZE19/Z1/+9/2/PN1e/p10/uo09dno"o1u peoe//:sdyy oy papeojumog + Topical negative pressure: Although some studies have demonstrated that this widely used treatment may safely improve healing of a diabetic foot ulcer, especially after a surgical procedure (eg, wide debridement or partial am- putation) [337-339], there is limited high-level evidence to support widespread utilization, especially in an infected wound [280, 340]. Only additional randomized clinical trials can establish when, for whom, and with what protocols these expensive ad- junctive therapies might be used in the treatment of the dia- betic foot ulcer. Limitations of the Literature and Future Studies. By mid-2011, >1800 papers had been published on some aspect of foot infections in persons with diabetes. We know a great deal about why diabetic patients develop foot infections, we have learned much about their epidemiology and pathophysiology, we know the usual causative organisms, we understand the role of surgical interventions, and we have demonstrated the effec- tiveness of many antimicrobial agents. And yet, the care of patients with this devastating problem is suboptimal in almost all settings. The main problem currently is less our lack of full understanding of the problem as our failure to apply what we know works. Based on the results of studies carried out in several settings in different countries, we know that about half of foot amputations can be avoided by improved care of a dia- betic foot ulceration or infection. Mainly, this means applying the basic principles outlined in this guideline (and those of other organizations). Clearly, the best way to ensure that these principles are applied is for the patient to be seen by some type of a multidisciplinary foot care team. What, then, are the limitations of the literature? Before the past decade we did not have a common language, so it was difficult to know what kinds of patients had been studied in a published report. In this regard, using one of several classifi- cation schemes, and specifically the IDSA or IWGDF infection severity classification, has helped. A major problem with studies of the microbiology of DFIs has been their failure to require optimal (ie, tissue) specimens for culture, and to some degree, the failure to properly culture for obligate anaerobes. In studies of antimicrobial therapy, the limitation has been the paucity, until the past decade, of randomized controlled trials. Unfortunately, these trials almost always exclude patients with bone infection or an ischemic limb, leaving us with little evi- dence-based information on how to treat these patients. Finally, many of the studies of treatments for DFIs, as with other conditions, are sponsored by industry, raising concerns about potential bias in which products are tested, by what methods, and how the results are reported. Recommendations From the Panel for Future Work in This Field. Listed below are several areas related to DFI that the panel members think are in most need of further research, technological and commercial development, or improved edu- cational methods that may lead to better outcomes when treat- ing DFls. Implementation. 1. Deploying a multidisciplinary team reduces the likeli- hood and extent of lower extremity amputations in diabetic patients with a foot infection. Medical institutions, insurance companies, and other healthcare systems should encourage the development of the following: a. Rapid-response or “hot” teams that can provide appro- priate initial evaluation and recommendations for care. b. Diabetic foot specialty teams or centers of excellence to which patients can later be referred for further consultation, if necessary. These teams should be composed of experi- enced medical, surgical, or nursing providers, working with specified, evidence-based procedures. Optimally they should include a foot specialist, a vascular surgeon, and a wound care specialist; they should also include or have access to specialists in infectious diseases or clinical micro- biology and other disciplines (eg, diabetes, pharmacy). c. In communities where this is not practical, providers should seek telemedicine consultations from experts, or at least attempt to develop formal or informal consulting relationships, to ensure prompt evaluation and treatment by appropriate specialists, when needed. 2. We encourage healthcare organizations to develop systems to regularly audit various aspects of their processes and key outcomes of care for patients with DFls who are treated in their institutions. Organizations should then use the results of these audits to improve care and better outcomes. 3. Healthcare organizations should ensure that providers who evaluate and manage patients with DFls have ready access to the required diagnostic and therapeutic equipment (including a monofilament, scalpel, sterile metal probe, forceps, tissue scissors), as well as advanced imaging and vas- cular diagnostic equipment and specialists. 4. Healthcare organizations should ensure implementation Of measures to prevent spread of multidrug-resistant organ- isms in both inpatient and outpatient settings, and we encou- rage providers to monitor bacterial resistance patterns of diabetic foot isolates. Regulatory Changes. 1. The FDA previously had a specific pathway for manufac- turers of new and approved antibiotics to apply for approval for treatment of “complicated skin and skin structure infec- tions including DFIs.” Their recently issued draft guidance for acute bacterial skin and skin structure infections specifically excludes patients with DFIs from enrollment in clinical trials, suggesting that sponsors wishing to develop a drug for this el62 » CID 2012:54 (15 June) e Lipsky et al 1ZOZ J9quiajdas gL uo jsanB Aq 696SSh/ZE19/Z1/+9/2/PN1e/p10/uo09dno"o1u peoe//:sdyy oy papeojumog indication consult with the FDA [160]. We encourage the FDA (and similar agencies in other countries) to clarify its re- quirements for studying DFIs, and the pharmaceutical compa- nies to invest in testing for antimicrobial agents for the DFI designation. 2. Many DFIs are complicated by bone involvement, yet there are no specific guidelines for conducting studies of treatment of this problem. Thus, we encourage the EDA (and similar agencies in other countries) to develop “Guidance for Industry” on con- ducting studies of antibiotic agents for treating osteomyelitis. 3. We encourage regulatory and oversight agencies, both local and national, to encourage (and ultimately require) healthcare organizations to tabulate and evaluate rates of foot complications in their diabetic population, to compare them to other sites, and to strive to improve outcomes. 4. We encourage various agencies that fund research pro- grams to invest in studies of this large and growing problem, including developing calls for proposals on the most needed subjects of research. Research Questions. 1. In an era of increasing antibiotic resistance, we must address several questions concerning the most appropriate antibiotic therapy for various types of DFls: a. Is there a role for treating clinically uninfected foot wounds with antimicrobials, either to prevent active in- fection or hasten wound healing? b. For which, if any, wounds are topical antimicrobial agents appropriate therapy? c. In which situations, and for how long, is parenteral (rather than oral) antibiotic therapy needed for a DF? d. What total duration of antibiotic therapy (topical, oral, or parenteral) is needed for various types of DFIs? e. Is it necessary to select an antibiotic regimen that covers all proven or suspected pathogens in a DFI? Is narrow-spectrum therapy safe and effective for selected types of infections? 2. Managing proven or presumed osteomyelitis is the most contentious aspect of treatment of DFIs. We encourage re- search that addresses these issues: a. What are the best clinical and imaging criteria (alone or in combinations) to diagnose bone infection? b. When is it appropriate to obtain a specimen of bone for culture (and histology, if possible) in a patient with sus- pected osteomyelitis? What are the best methods to obtain such a specimen, and how can we persuade reluctant specialists to perform the procedure? c. When is surgical resection of infected or necrotic bone most appropriate? d. What is the required duration of antimicrobial treat- ment of osteomyelitis, both in patients who have, and have not, undergone surgical resection of infected or ne- crotic bone? e. What diagnostic studies can help determine when osteomyelitis has been arrested after treatment? 3. Various types of adjunctive therapies (eg, antibiotic loaded poly[methyl methacrylate] beads, hyperbaric oxygen, and G-CSF) may have some benefit in selected patients; we need to define for which, if any, patients these treatments are cost-effective. 4. Biofilm appears to play an important role in increasing the difficulty of treating DFIs. What are the best ways to try to elimin- ate biofilm or make bacteria in biofilm easier to eradicate? PERFORMANCE MEASURES Clinicians caring for patients with a DFL, and their patients, need assurance that the care they are providing (or receiving) is of acceptable quality. For this reason, and to drive service im- provement, clinicians and organizations should undertake measures of both outcome and process, and make them avail- able for review, benchmarking, and action planning (Table 14). Currently, there is considerable variability in care pathways and processes, even within similar organizations, but particularly across different types of healthcare systems. We think clinicians should attempt to compare their key outcomes to those of Table 14. Potential Performance Measures for Managing betic Foot Infection Outcomes of Treatment + What percentage of treated patients had their infection eradicated? + What percentage of treated patients underwent an amputation (and at what level) or other substantial surgical procedure (eg, bone resection)? + What percentage of patients suffered clinically significant adverse effects from their treatment? + What percentage of patients were alive; antibiotic free; ulcer free at various intervals (and at least 12 mo after treatment)? Process of management + Did appropriate clinicians evaluate the patient (eg, foot surgeon, vascular surgeon, infectious diseases or clinical microbiology specialist, wound care specialist)? + How long did it take before the patient was seen by a foot specialist or team? + Were appropriate specimens taken for culture from infected wounds? + Was the selected antibiotic regimen appropriate (empiric and definitive choices, changes in regimen when needed, duration of treatment)? + Was appropriate outpatient follow-up arranged after acute care? + Does the service have protocols to assist and define the functioning of the multidisciplinary team, the process of antibiotic selection, and antibiotic duration in different situations? IDSA Guideline for Diabetic Foot Infections e CID 2012:54 (15 June) + el63 1ZOZ J9quiajdas gL uo jsanB Aq 696SSh/ZE19/Z1/+9/2/PN1e/p10/uo09dno"o1u peoe//:sdyy oy papeojumog 45, 47. 48. 49, 50. 51. 5: 53. 54, 55. 56. 57. 58. 59. 6l. from non-infected diabetic foot ulcers: a pilot study. Diabetología 2008; 51:347-52. . Wagner FW Jr. The dysvascular foot: a system for diagnosis and treatment. Foot Ankle 1981; 2:64-122. Treece KA, Macfarlane RM, Pound N, Game EL, Jeffcoate WJ. Vali- dation of a system of foot ulcer classification in diabetes mellitus. Diabet Med 2004; 21:987-91. Ince P, Kendrick D, Game E, Jefícoate W. The association between baseline characteristics and the outcome of foot lesions in a UK population with diabetes. Diabet Med 2007; 24:977-81. Armstrong DG, Lavery LA, Harkless LB. Validation of a diabetic wound — classification system. The contribution of depth, infection, and ischemia to risk of amputation. Diabetes Care 1998; 21:855-9. Parisi MC, Zantut-Witmann DE, Pavin EJ, Machado H, Nery M, Jefícoate W]. Comparison of three systems of classification in pre- dicting the outcome of diabetic foot ulcers in a Brazilian population. Eur ] Endocrinol 2008; 159:417-22. Knighton DR, Ciresi KF, Fiegel VD, Austin LL, Butler EL. Classifi- cation and treatment of chronic nonhealing wounds. Successful treat- ment with autologous platelet-derived wound healing factors (PDWHF). Ann Surg 1986; 204:322-30. Beckert S, Witte M, Wicke C, Konigsrainer A, Coerper S. A new wound-based severity score for diabetic foot ulcers: a prospective analysis of 1,000 patients. Diabetes Care 2006; 29:988-92. Beckert S, Pietsch AM, Kuper M, et al. M.A.L.D.: a prognostic score estimating probability of healing in chronic lower extremity wounds. Ann Surg 2009; 249:677-81. Lipsky BA, Polis AB, Lantz KC, Norquist JM, Abramson MA. The value of a wound score for diabetic foot infections in predicting treatment outcome: a prospective analysis from the SIDESTEP trial. Wound Repair Regen 2009; 17:671-7. Lipsky BA, Berendt AR, Deery HG, et al. Diagnosis and treatment of diabetic foot infections. Clin Infect Dis 2004; 39:885-910. Schaper NC, Apelqvist J, Bakker K. The international consensus and practical guidelines on the management and prevention of the dia- betic foot. Curr Diab Rep 2003; 3:475-9. Shah BR, Hux JE. Quantifying the risk of infectious diseases for people with diabetes. Diabetes Care 2003; 26:510-3. Vedhara K, Miles JN, Wetherell MA, et al. Coping style and depression influence the healing of diabetic foot ulcers: observational and mechanistic evidence, Diabetologia 2010; 53:1590-8. Uzun G, Solmazgul E, Curuksulu H, et al. Procalcitonin as a diag- nostic aid in diabetic foot infections. Tohoku J Exp Med 2007; 213:305-12. Lipsky BA, Sheehan P, Armstrong DG, Tice AD, Polis AB, Abramson MA. Clinical predictors of treatment failure for diabetic foot infections: data from a prospective trial. Int Wound J 2007; 4:30-8. Akinci B, Yener S, Yesil S, Yapar N, Kucukyavas Y, Bayraktar F. Acute phase reactants predict the risk of amputation in diabetic foot infection. J Am Podiatr Med Assoc 2011; 101:1-6. . Peripheral arterial disease in people with diabetes. Diabetes Care 2003; 26:3333-41. Hirsch AT, Haskal ZJ, Hertzer NR, et al. ACC/AHA 2005 Practice Guidelines for the management of patients with peripheral arterial disease (lower extremity, renal, mesenteric, and abdominal aortic): a collaborative report from the American Association for Vascular Surgery/Society for Vascular Surgery, Society for Cardiovascular An- giography and Interventions, Society for Vascular Medicine and Biology, Society of Interventional Radiology, and the ACC/AHA. Task Force on Practice Guidelines (Writing Committee to Develop Guidelines for the Management of Patients With Peripheral Arterial Disease): endorsed by the American Association of Cardiovascular and Pulmonary Rehabilitation; National Heart, Lung, and Blood In- stitute; Society for Vascular Nursing; TransAtlantic Inter-Society 62. 63. 65. 67. 68. 69. 7 7 7. 7. 74. 75. 76. 77. 78. 79. 80. 8L. 82. 83. 2 Consensus; and Vascular Disease Foundation. Circulation 2006; 113: ed63-654, van Baal JG. Surgical treatment of the infected diabetic foot. Clin Infect Dis 2004; 39(Suppl 2):5123-8. Pinzur MS, Pinto MA, Schon LC, Smith DG. Controversies in ampu- tation surgery. Instr Course Lect 2003; 52:445-51. Khan NA, Rahim SA, Anand SS, Simel DL, Panju A. Does the clini- cal examination predict lower extremity peripheral arterial disease? JAMA 2006; 295:536-46. Wilson JF, Laine C, Goldmann D. In the clinic. Peripheral arterial disease. Ann Intern Med 2007; 146.TC3-1-ITC3-16. Crane M, Werber B. Critical pathway approach to diabetic pedal in- fections in a multidisciplinary setting. J Foot Ankle Surg 1999; 38:30-3; discussion 82-3. Larsson J, Apelqvist J, Agardh CD, Stenstrom A. Decreasing incidence of major amputation in diabetic patients: a consequence of a multidis- ciplinary foot care team approach? Diabet Med 1995; 12:770-6. Dargis V, Pantelejeva O, Jonushaite A, Vileikyte L, Boulton AJ. Benefits of a multidisciplinary approach in the management of recur- rent diabetic foot ulceration in Lithuania: a prospective study. Dia- betes Care 1999; 22:1428-31. Fitygerald RH, Mills JL, Joseph W, Armstrong DG. The diabetic rapid response acute foot team: 7 essential skills for targeted limb salvage. Eplasty 2009; 9: Gibbons GW. Lower extremity bypass in patients with diabetic foot ulcers. Surg Clin North Am 2003; 83:659-69. . Bus SA, Hazenberg CE, Klein M, Van Baal JG. Assessment of foot disease in the home environment of diabetic patients using a new photographic foot imaging device. ] Med Eng Technol 2010; 34:43-50. Clemensen J, Larsen SB, Ejskjaer N. Telemedical treatment at home of diabetic foot ulcers. ] Telemed Telecare 2005; 11(Suppl 2):514-6. Bowling FL, King L, Paterson JA, et al. Remote assessment of dia- betic foot ulcers using a novel wound imaging system. Wound Repair Regen 2011; 1925-30. Wilbright WA, Birke JA, Patout CA, Varnado M, Horswell R. The use of telemedicine in the management of diabetes-related foot ul- ceration: a pilot study. Adv Skin Wound Care 2004; 17:232-8. Aragon-Sanchez J. Seminar review: a review of the basis of surgical treatment of diabetic foot infections. Int J Low Extrem Wounds 2011; 10:33-65. Sumpio BE, Armstrong DG, Lavery LA, Andros G. The role of inter- disciplinary team approach in the management of the diabetic foot: a joint statement from the Society for Vascular Surgery and the Amer- ican Podiatric Medical Association. ] Vasc Surg 2010; 51:1504-6. Akbari CM, Pomposelli EB Jr, Gibbons GW, et al. Lower extremity revascularization in diabetes: late observations. Arch Surg 2000; 135:452-6. Lipsky BA, Pecoraro RE, Larson SA, Hanley ME, Ahroni JH. Outpa- tient management of uncomplicated lower-extremity infections in diabetic patients. Arch Intern Med 1990; 150:790-7. Lipsky BA, Itani K, Norden C. Treating foot infections in diabetic patients: a randomized, multicenter, open-label trial of linezolid versus ampicillin-sulbactam/amoxicillin-clavulanate. Clin Infect Dis 2004; 38:17-24. Armstrong DG, Lavery LA, Sariaya M, Ashry H. Leukocytosis is a poor indicator of acute osteomyelitis of the foot in diabetes mellitus. J Foot Ankle Surg 1996; 35:280-3. Eneroth M, Larsson J, Apelgvist J. Deep foot infections in patients with diabetes and foot ulcer: an entity with different characteristics, treatments, and prognosis. ] Diabetes Complications 1999; 13:254-63, Frykberg RG. An evidence-based approach to diabetic foot infec- tions. Am ] Surg 2003; 186:445-545; discussion 615-645. Caputo GM, Cavanagh PR, Ulbrecht JS, Gibbons GW, Karchmer AW. Assessment and management of foot disease in patients with diabetes. N Engl J Med 1994; 331:854-60. el66 » CID 2012:54 (15 June) e Lipsky et al 1ZOZ J9quiajdas gL uo jsanB Aq 696SSh/ZE19/Z1/+9/2/PN1e/p10/uo09dno"o1u peoe//:sdyy oy papeojumog 84. 8: 86. 8: 88. 8 9 9. 9: 9, 9, 95. 96. 97. 98. 99. 100. 101. 102. 103. 104, 105. 106. S No authors listed. Consensus Development Conference on Diabetic Foot Wound Care: 7-8 April 1999, Boston, Massachusetts. American Diabetes Association. Diabetes Care 1999; 22:1354-60. Rao N, Lipsky BA. Optimising antimicrobial therapy in diabetic foot infections. Drugs 2007; 67:195-214. Dang CN, Prasad YD, Boulton AJ, Jude EB. Methicillin-resistant Sta- phylococcus aureus in the diabetic foot clinic: a worsening problem. Diabet Med 2003; 20:159-61. Stanaway S, Johnson D, Moulik P, Gill G. Methicillin-resistant Staphy- lococcus aureus (MRSA) isolation from diabetic foot ulcers correlates with nasal MRSA carriage. Diabetes Res Clin Pract 2007; 75:47-50. Carvalho CB, Neto RM, Aragao LP, Oliveira MM, Nogueira MB, Forti AC. [Diabetic foot infection. Bacteriologic analysis of 141 patients]. Arq Bras Endocrinol Metabol 2004; 48:398-405. Shankar EM, Mohan V, Premalatha G, Srinivasan RS, Usha AR. Bac- terial etiology of diabetic foot infections in South India. Eur ] Intern Med 2005; 16:567-70. Tascini C, Gemignani G, Palumbo E, et al. Clinical and microbiologi- cal efficacy of colistin therapy alone or in combination as treatment for multidrug resistant Pseudomonas aeruginosa diabetic foot infec- tions with or without osteomyelitis. J Chemother 2006; 18:648-51. Kandemir O, Akbay E, Sahin E, Milcan A, Gen R. Risk factors for infection of the diabetic foot with multi-antibiotic resistant microor- ganisms. ] Infect 2007; 54:439-45, Gadepalli R, Dhawan B, Sreenivas V, Kapil A, Ammini AC, Chaudhry R. A clinico-microbiological study of diabetic foot ulcers in an Indian tertiary care hospital. Diabetes Care 2006; 29:1727-32. Edmonds M. Infection in the neuroischemic foot. Int J low Extrem Wounds 2005; 4:145-53. Richard JL, Sotto A, Jourdan N, et al. Risk factors and healing impact of multidrug-resistant bacteria in diabetic foot ulcers. Dia- betes Metab 2008; 34:363-9. Sotto A, Richard JL, Jourdan N, Combescure C, Bouziges N, Lavigne JP. Miniaturized oligonudeotide arrays: a new tool for discriminating colonization from infection due to Staphylococcus aureus in diabetic foot ulcers. Diabetes Care 2007; 30:2051-6. Chakraborti C, Le C, Yanofsky A. Sensitivity of superficial cultures in lower extremity wounds. ] Hosp Med 2010; 5:415-20. Gardner SE, Frantz RA, Saltzman CL, Hillis SL, Park H, Scherubel M. Diagnostic validity of three swab techniques for identifying chronic wound infection. Wound Repair Regen 2006; 14:548-57. Nelson EA, O'Meara S, Craig D, et al. A series of systematic reviews to inform a decision analysis for sampling and treating infected dia- betic foot ulcers. Health Technol Assess 2006; 10:ii-iv, ix-x, 1-221. Singh SK, Gupta K, Tiwari S, et al. Detecting aerobic bacterial diver- sity in patients with diabetic foot wounds using ERIC-PCR: a pre- liminary communication. Int J Low Extrem Wounds 2009; 8:203-8. Fisher TK, Wolcott R, Wolk DM, Bharara M, Kimbriel HR, Arm- strong DG. Diabetic foot infections: a need for innovative assess- ments. Int ] Low Extrem Wounds 2010; 931-6. Sotto A, Lina G, Richard JL, et al. Virulence potential of Staphylococ- cus aureus strains isolated from diabetic foot ulcers: a new paradigm. Diabetes Care 2008; 31:2318-24. Wolcott RD, Cox SB, Dowd SE. Healing and healing rates of chronic wounds in the age of molecular pathogen diagnostics. ] Wound Care 2010; 19:272-8, 80-1. Hirschl M, Hirschl AM. Bacterial flora in mal perforant and antimi- crobial treatment with ceftriaxone. Chemotherapy 1992; 38:275-80. Chantelau E, Tanudjaja T, Altenhofer E Ersanli Z, Lacigova S, Metzger C. Antibiotic treatment for uncomplicated neuropathic fore- foot ulcers in diabetes: a controlled trial. Diabet Med 1996; 13:156-9. Edmonds M, Foster A. The use of antibiotics in the diabetic foot. Am ] Surg 2004; 187:25-285. Gardner SE, Frantz RA. Wound bioburden and infection-related complications in diabetic foot ulcers. Biol Res Nurs 2008; 10:44-53. 107. 108. 10% 110. 1 112. 113, 114. 115. 116. 17. 118. 119. 120. 121. 122. 123. 124. 125. 126. Ramakant P, Verma AK, Misra R, et al. Changing microbiological profile of pathogenic bacteria in diabetic foot infections: time for a rethink on which empirical therapy to choose? Diabetologia 2011; 54:58-64. Lipsky BA. Empirical therapy for diabetic foot infections: are there clinical dues to guide antibiotic selection? Clin Microbiol Infect 2007; 13:351-3. . Wheat LJ, Allen SD, Henry M, et al. Diabetic foot infections. Bacter- iologic analysis. Arch Intern Med 1986; 146:1935-40. Krikava K, Pospisil M. [The diabetic foot syndrome—antibiotic therapy]. Rozhl Chir 1999; 78:295-8. Ng LS, Kwang LL, Yeow SC, Tan TY. Anaerobic culture of diabetic foot infections: organisms and antimicrobial susceptibilities. Ann Acad Med Singapore 2008; 37:936-9. Dowd SE, Wolcott RD, Sun Y, McKeehan T, Smith E, Rhoads D. Polymicrobial nature of chronic diabetic foot ulcer biofilm infections determined using bacterial tag encoded FLX amplicon pyrosequen- cing (bTEFAP). PLoS One 2008; 3:e3326. Armstrong DG, Liswood PJ, Todd WE, William J. Stickel Bronze Award. Prevalence of mixed infections in the diabetic pedal wound. A retrospective review of 112 infections. J Am Podiatr Med Assoc 1995; 85:533-7. Lipsky BA, Holroyd KJ, Zasloff M. Topical versus systemic antimi- crobial therapy for treating mildly infected diabetic foot ulcers: a ran- domized, controlled, double-blinded, multicenter trial of pexiganan cream. Clin Infect Dis 2008; 47:1537-45. Lipsky BA, Hoey C. Topical antimicrobial therapy for treating chronic wounds. Clin Infect Dis 2009; 49:1541-9. Lipsky BA, McDonald D, Litka P. Treatment of infected diabetic foot ulcers: topical MSI-78 vs. oral ofloxacin. Diabetologia 1997; 40:482. Noel GJ, Strauss RS, Amsler K, Heep M, Pypstra R, Solomkin JS. Results of a double-blind, randomized trial of ceftobiprole treatment of complicated skin and skin structure infections caused by gram- positive bacteria. Antimicrob Agents Chemother 2008; 52:37-44. Noel GJ, Bush K, Bagchi P, lanus J, Strauss RS. A randomized, double-blind trial comparing ceftobiprole medocaril with vancom: cin plus ceftazidime for the treatment of patients with comp) cated skin and skin-structure infections. Clin Infect Dis 2008; 46:647-55. Graham DR, Lucasti C, Malafaia O, et al. Ertapenem once daily versus piperacillin-tazobactam 4 times per day for treatment of com- plicated skin and skin-structure infections in adults: results of a pro- spective, randomized, double-blind multicenter study. Clin Infect Dis 2002; 34:1460-8. Lipsky BA, Armstrong DG, Citron DM, Tice AD, Morgenstern DE, Abramson MA. Ertapenem versus piperacillin/tazobactam for dia- betic foot infections (SIDESTEP): prospective, randomised, con- trolled, double-blinded, multicentre trial. Lancet 2005; 366:1695-703. Ertugrul MB, Baktiroglu S, Salman S, et al. Pathogens isolated from deep soft tissue and bone in patients with diabetic foot infections. J Am Podiatr Med Assoc 2008; 98:290-5. Martinez-Gomez Dde A, Ramirez-Almagro C, Campillo-Soto A, Morales-Cuenca G, Pagan-Ortiz J, Aguayo-Albasini JL. [Diabetic foot infections. Prevalence and antibiotic sensitivity of the causative microorganisms]. Enferm Infecc Microbiol Clin 2009; 27:317-21. Bansal E, Garg A, Bhatia S, Attri AK, Chander J. Spectrum of microbial flora in diabetic foot ulcers. Indian J Pathol Microbiol 2008; 51:204-8. Yoga R, Khairul A, Sunita K, Suresh C. Bacteriology of diabetic foot lesions. Med J Malaysia 2006; 61(Suppl A):14-6. Shakil S, Khan AU. Infected foot ulcers in male and female diabetic : a clinico-bioinformative study. Ann Clin Microbiol Antimi- Wang SH, Sun ZL, Guo Y], et al. Meticillin-resistant Staphylococcus aureus isolated from foot ulcers in diabetic patients in a Chinese care IDSA Guideline for Diabetic Foot Infections e CID 2012:54 (15 June) + el67 1ZOZ J9quiajdas gL uo jsanB Aq 696SSh/ZE19/Z1/+9/2/PN1e/p10/uo09dno"o1u peoe//:sdyy oy papeojumog 12: 12: 12: 130. 131 132. 133. 134. 135. 136. 137. 138. 139. 141. 142. 143. 145. hospital: risk factors for infection and prevalence. ] Med Microbiol 2010; 59:1219-24. Tentolouris N, Petrikkos G, Vallianou N, et al. Prevalence of methi- cillin-resistant Staphylococcus aureus in infected and uninfected dia- betic foot ulcers. Clin Microbiol Infect 2006; 12:186-9. Yates C, May K, Hale T, et al. Wound chronicity, inpatient care, and chronic kidney disease predispose to MRSA infection in diabetic foot ulcers. Diabetes Care 2009; 32:1907-9. Vardakas KZ, Horianopoulou M, Falagas ME. Factors associated with treatment failure in patients with diabetic foot infections: an analysis of data from randomized controlled trials. Diabetes Res Clin Pract 2008; 80:344-51. Arbeit RD, Maki D, Tally FP, Campanaro E, Eisenstein BL. The safety and efficacy of daptomycin for the treatment of complicated skin and skin-structure infections. Clin Infect Dis 2004; 38:1673-81. Eleftheriadou 1, Tentolouris N, Argiana V, Jude E, Boulton AJ. Methicillin-resistant Staphylococcus aureus in diabetic foot infections. Drugs 2010; 70:1785-97. Liu C, Bayer A, Cosgrove SE, et al. Clinical practice guidelines by the infectious diseases society of america for the treatment of methicil- lin-resistant Staphylococcus aureus infections in adults and children. Clin Infect Dis 2011; 52:e18-55. David MZ, Glikman D, Crawford SE, et al. What is community- associated methicillin-resistant Staphylococcus aureus? J Infect Dis 2008; 197:1235-43. Lagace-Wiens PR, Ormiston D, Nicolle LE, Hilderman T, Embil J. The diabetic foot clinic: not a significant source for acquisition of methicillin-resistant Staphylococcus aureus. Am J Infect Control 2009; 37:587-9. Raymakers JT, Schaper NC, van der Heyden JJ, Tordoir JH, Kitslaar PJ. Penetration of ceftazidime into bone from severely ischaemic limbs. ] Antimicrob Chemother 1998; 42:543-5. Seabrook GR, Edmiston CE, Schmitt DD, Krepel C, Bandyk DE, Towne JB. Comparison of serum and tissue antibiotic levels in dia- betes-related foot infections. Surgery 1991; 110:671-6; discussion 76-7. Duckworth C, Fisher JE, Carter SA, et al. Tissue penetration of clin- damycin in diabetic foot infections. J Antimicrob Chemother 1993; 31:581-4. Legat FJ, Maier A, Dittrich P, et al. Penetration of fosfomycin into inflammatory lesions in patients with cellulitis or diabetic foot syn= drome. Antimicrob Agents Chemother 2003; 47371-4. Muller M, Brunner M, Hollenstein U, et al. Penetration of ciproflox- acin into the interstitial space of inflamed foot lesions in non- insulin-dependent diabetes mellitus patients. Antimicrob Agents Chemother 1999; 43:2056-8. |. Kuck EM, Bouter KP, Hoekstra JB, Conemans JM, Diepersloot RJ. Tissue concentrations after a single-dose, orally administered ofloxacin in patients with diabetic foot infections. Foot Ankle Int 1998; 1%: 38-40. Mueller-Buehl U, Diehm C, Gutzler E, Adam D. Tissue concen- trations of ofloxacin in necrotic foot lesions of diabetic and non-dia- betic patients with peripheral arterial occlusive disease. Vasa 1991; 20:17-21. Traunmuller E, Schintler MV, Metzler J, et al. Soft tissue and bone penetration abilities of daptomycin in diabetic patients with bacterial foot infections. ] Antimicrob Chemother 2010; 65:1252-7. Schintler MV, Traunmuller F, Metzler J, et al. High fosfomycin con- centrations in bone and peripheral soft tissue in diabetic patients pre= senting with bacterial foot infection. J Antimicrob Chemother 2009; 64:574-8. .. Majcher-Peszynska J, Haase G, Sass M, et al. Pharmacokinetics and penetration of linezolid into inflamed soft tissue in diabetic foot infections. Eur ] Clin Pharmacol 2008; 64:1093-100. Nicolau DP, Stein GE. Therapeutic options for diabetic foot infec- tions: a review with an emphasis on tissue penetration characteristics. J Am Podiatr Med Assoc 2010; 100:52-63. 147. 148. 149. 150. 151. 152. 15: 154, 155. 156. 157. 151 159. 161. 162. . Raymakers JT, Houben AJ, van der Heyden JJ, Tordoir JH, Kitslaar PJSchaper NC. The effect of diabetes and severe ischaemia on the penetration of ceftazidime into tissues of the limb. Diabet Med 2001; 18:229-34, Deresinski SC. The efficacy and safety of ceftobiprole in the treat- ment of complicated skin and skin structure infections: evidence from 2 clinical trials. Diagn Microbiol Infect Dis 2008; 61:103-9. Lipsky BA, Giordano P, Choudhri S, Song J. Treating diabetic foot infections with sequential intravenous to oral moxifloxacin compared with. piperacillin-tazobactam/amoxicillin-clavulanate. J Antimicrob Chemother 2007; 60:370-6. Harkless L, Boghossian J, Pollak R, et al. An open-label, randomized study comparing efficacy and safety of intravenous piperacillin/tazo- bactam and ampicillin/sulbactam for infected diabetic foot ulcers. Surg Infect (Larchmt) 2005; 6:27-40. Clay PG, Graham MR, Lindsey CC, Lamp KC, Freeman C, Glaros A. Clinical efficacy, tolerability, and cost savings associated with the use of open-label metronidazole plus ceftriaxone once daily compared with ticarcillin/clavulanate every 6 hours as empiric treatment for diabetic lower-extremity infections in older males. Am J Geriatr Pharmacother 2004; 2:181-9. Lobmann R, Ambrosch A, Seewald M, et al. Antibiotic therapy for diabetic foot infections: comparison of cephalosporines with chino- lones. Diabetes Nutr Metab 2004; 17:156-62. Vick-Fragoso R, Hernandez-Oliva G, Cruz-Alcazar J, et al. Efficacy and safety of sequential intravenous/oral moxifloxacin vs intrave- nous/oral amoxicillin/davulanate for complicated skin and skin structure infections. Infection 2009; 37:407-17. .. Griffis CD, Metcalfe S, Bowling FL, Boulton AJ, Armstrong DG. The use of gentamycin-impregnated foam in the management of diabetic foot infections: a promising delivery system? Expert Opin Drug Deliv 2009; 6:639-42. Salgami EV, Bowling EL, Whitehouse RW, Boulton AJ. Use of tobra- mycin-impregnated calcium sulphate pellets in addition to oral anti- biotics: an alternative treatment to minor amputation in a case of diabetic foot osteomyelitis. Diabetes Care 2007; 30:181-2. Lipsky BA, Stoutenburgh U. Daptomycin for treating infected di betic foot ulcers: evidence from a randomized, controlled trial com- paring daptomycin with vancomycin or semi-synthetic penicillins for complicated skin and skin-structure infections. ] Antimicrob Chemother 2005; 55:240-5. Sabol M. Phase 3 study: evaluating the safety and efficacy of a once- daily dose of tigecycline and ertapenem in diabetic foot infections with a substudy in patients with diabetic foot infections complicated by osteomyelitis. 2009; Clinical Trials Identifier Number: NCTO0366249. Saltoglu N, Dalkiran A, Tetiker T, et al. Piperacillin/tazobactam versus imipenem/cilastatin for severe diabetic foot infections: a pro- spective, randomized clinical trial in a university hospital. Clin Mi- crobiol Infect 2010; 16:1252-7. .. No authors listed. Study evaluating the safety and efficacy of a once- daily dose of tigecycline vs ertapenem in diabetic foot infections (DEL) with a substudy in patients with diabetic foot infections com- plicated by osteomyelitis. 2010. Lipsky BA. Evidence-based antibiotic therapy of diabetic foot infec- tions. FEMS Immunol Med Microbiol 1999; 26:267-76. |. No authors listed. Guidance for industry. Acute bacterial skin and skin structure infections: developing drugs for treatment DRAFT GUIDANCE. US Department of Health and Human Services Food and Drug Administration Center for Drug Evaluation and Research (CDER) 2010; Docket Number HFA-305:1-35. Crouzet J, Lavigne JP, Richard JL, Sotto A. Diabetic foot infection: a critical review of recent randomized clinical trials on antibiotic therapy. Int J Infect Dis 2011; 15:e601-10. Dinh MT, Abad CL, Safdar N. Diagnostic accuracy of the physical examination and imaging tests for osteomyelitis underlying diabetic foot ulcers: meta-analysis. Clin Infect Dis 2008; 47:519-27. el68 » CID 2012:54 (15 June) e Lipsky et al 1ZOZ J9quiajdas gL uo jsanB Aq 696SSh/ZE19/Z1/+9/2/PN1e/p10/uo09dno"o1u peoe//:sdyy oy papeojumog 253. 254, 255, 256. 25; 258. 259, 260. 261. 262. 263. 264, 265. 266. 267. 268. 269, 270. 271. 272. 273. 274, 275. 276. 277. 278. Lavery LA, Armstrong DG, Quebedeaux TL, Walker SC. Puncture wounds: normal laboratory values in the face of severe infection in diabetics and non-diabetics. Am J Med 1996; 101:521-5. Tan JS, Friedman NM, Hazelton-Miller C, Flanagan JP, File TM Jr. Can aggressive treatment of diabetic foot infections reduce the need for above-ankle amputation? Clin Infect Dis 1996; 23:286-91. Armstrong DG, Lipsky BA. Diabetic foot infections: stepwise medical and surgical management. Int Wound J 2004; 1:123-32. Grodinsky M. A study of the fascial spaces of the foot and their bearing on infections. 1929:737-43. Loeffler RD Jr, Ballard A. Plantar fascial spaces of the foot and a proposed surgical approach. Foot Ankle 1980; 1:11-4. Piaggesi A, Schipani E, Campi E, et al. Conservative surgical ap- proach versus non-surgical management for diabetic neuropathic foot ulcers: a randomized trial. Diabet Med 1998; 15:412-7. Bose K. A surgical approach for the infected diabetic foot. Int Orthop 1979; 3:177-81. Brodsky JW, Schneidler C. Diabetic foot infections. Orthop Clin North Am 1991; 22:473-89. Connolly JE, Wrobel JS, Anderson RF. Primary closure of infected diabetic foot wounds. A report of dosed instillation in 30 cases. ] Am Podiatr Med Assoc 2000; 90:175-82. Pinzur MS. Amputation level selection in the diabetic foot. Clin Orthop Relat Res 1993:68-70. Armstrong DG, Lavery LA, Erykberg RG, Wu SC, Boulton AJ. Vali- dation of a diabetic foot surgery classification. Int Wound J 2006; 3:240-6. Durham JR, McCoy DM, Sawchuk AP, et al. Open transmetatarsal amputation in the treatment of severe foot infections. Am ] Surg 1989; 158:127-30. Benton GS, Kerstein MD. Cost effectiveness of early digit amputation in the patient with diabetes. Surg Gynecol Obstet 1985; 161:523-4. Field CK, Kerstein MD. Cost-benefit analysis of lower-extremity am- putation: ethical considerations. Wounds 1993; 5:10-3. Van Damme H, Rorive M, Martens De Noorthout BM, Quaniers J, Scheen A, Limet R. Amputations in diabetic patients: a plea for foot- sparing surgery. Acta Chir Belg 2001; 101:123-9. Khammash MR, Obeidat KA. Prevalence of ischemia in diabetic foot infection. World ] Surg 2003; 27:797-9. Wrobel JS, Robbins J, Armstrong DG. The high-low amputation ratio: a deeper insight into diabetic foot care? ] Foot Ankle Surg 2006; 45:375-9. Jones V. Debridement of diabetic foot lesions. The Diabetic Foot 1998; 1:88-94. Rauwerda JA. Foot debridement: anatomic knowledge is mandatory. Diabetes Metab Res Rev 2000; 16(Suppl 1):523-6. Lepantalo M, Biancari F, Tukiainen E. Never amputate without con- sultation of a vascular surgeon. Diabetes Metab Res Rev 2000; 16 (Suppl 1):527-32. LoGerfo FW, Coffman JD. Current concepts. Vascular and microvas- cular disease of the foot in diabetes. Implications for foot care. N Engl ] Med 1984; 311:1615-9. Holstein PE, Sorensen S. Limb salvage experience in a multidisciplin- ary diabetic foot unit. Diabetes Care 1999; 22(Suppl 2):B97-103. Estes JM, Pomposelli FB Jr. Lower extremity arterial reconstruction in patients with diabetes mellitus. Diabet Med 1996; 13(Suppl 1): $437. Chang BB, Darling RC 3rd, Paty PS, Lloyd WE, Shah DM, Leather RP. Expeditious management of ischemic invasive foot infections. Cardiovasc Surg 1996; 4:792-5. Taylor LM Jr, Porter JM. The clinical course of diabetics who require emergent foot surgery because of infection or ischemia. J Vasc Surg 1987; 6:454-9. Steed DL, Donohoe D, Webster MW, Lindsley L. Effect of extensive debridement and treatment on the healing of diabetic foot ulcers. Diabetic Ulcer Study Group. J Am Coll Surg 1996; 183:61-4. 279. 280. 28 282. 283. 284, 285, 286. 287. 288. 289, 290. 291. 292. 293. 294, 295. 296. 297. 298. 29: 300. Vermeulen H, Ubbink D, Goossens A, de Vos R, Legemate D. Dres- sings and topical agents for surgical wounds healing by secondary intention. Cochrane Database Syst Rev 2004; 2:CD003554. Ubbink DT, Westerbos SJ, Evans D, Land L, Vermeulen H. Topical negative pressure for treating chronic wounds. Cochrane Database Syst Rev 2008; 3:CD001898. . Vermeulen H, van Hattem JM, Storm-Versloot MN, Ubbink DT. Topical silver for treating infected wounds. Cochrane Database Syst Rev 2007; 1:CD005486. Bergin SM, Wraight P. Silver based wound dressings and topical agents for treating diabetic foot ulcers. Cochrane Database Syst Rev 2006; 1:CD005082. Hinchliffe RJ, Valk GD, Apelqvist J, et al. A systematic review of the effectiveness of interventions to enhance the healing of chronic ulcers of the foot in diabetes. Diabetes Metab Res Rev 2008; 24 (Suppl 1):5119-44. Hilton JR, Williams DT, Beuker B, Miller DR, Harding KG. Wound dressings in diabetic foot disease. Clin Infect Dis 2004; 39(Suppl 2): S100-3. Nelson EA, O'Meara $, Golder S, Dalton J, Craig D, Iglesias C. Sys- tematic review of antimicrobial treatments for diabetic foot ulcers. Diabet Med 2006; 23:348-59. O'Meara SM, Cullum NA, Majid M, Sheldon TA. Systematic review of antimicrobial agents used for chronic wounds. Br J Surg 2001; 88:4-21. Steed DL. Clinical evaluation of recombinant human platelet-derived growth factor for the treatment of lower extremity ulcers. Plast Re- constr Surg 2006; 117:143S-1495; discussion 505-515. Apelgvist J, Bakker K, van Houtum WH, Schaper NC. Practical guidelines on the management and prevention of the diabetic foot: based upon the International Consensus on the Diabetic Foot (2007) Prepared by the International Working Group on the Diabetic Foot. Diabetes Metab Res Rev 2008; 24(Suppl 1):5181-7. Driver VR. Treating the macro and micro wound environment of the diabetic patient: managing the whole patient, not the hole in the patient. 2004:49-56. Svensjo T, Pomahac B, Yao E Slama J, Eriksson E. Accelerated healing of full-+hickness skin wounds in a wet environment. Plast Reconstr Surg 2000; 106:602-12; discussion 13-4. Smith J, Thow J. ls debridement effective for diabetic foot ulcers? A systematic review: 2. The Diabetic Foot 2001; 4:77-80. Smith J. Is debridement effective for diabetic foot ulcer? A systematic review: 1. The Diabetic Foot 2001; 1:10-4. Eldor R, Raz 1, Ben Yehuda A, Boulton AJ. New and experimental ap- proaches to treatment of diabetic foot ulcers: a comprehensive review of emerging treatment strategies. Diabet Med 2004; 21:1161-73. Cutting K, White R, Edmonds M. The safety and efficacy of dressings with silver—addressing clinical concerns. Int Wound ] 2007; 4:177-84. Chopra L The increasing use of silver-based products as antimicro- bial agents: a useful development or a cause for concern? ] Antimi- crob Chemother 2007; 59:587-90. Percival SL, Woods E, Nutekpor M, Bowler P, Radford A, Cochrane C. Prevalence of silver resistance in bacteria isolated from diabetic foot ulcers and efficacy of silver-containing wound dressings. Ostomy Wound Manage 2008; 54:30-40. Silver dressings for the treatment of patients with infected wounds: a review of clinical and cost-effectiveness. Health Technology Inquiry Service, 2010. Storm-Versloot MN, Vos CG, Ubbink DT, Vermeulen H. Topical silver for preventing wound infection. Cochrane Database Syst Rev 2010; 3:CD006478. . Armstrong DG, Nguyen HC, Lavery LA, van Schie CH, Boulton AJ, Harkless LB. Off-loading the diabetic foot wound: a randomized clinical trial. Diabetes Care 2001; 24:1019-22. Lewis R, Whiting P, ter Riet G, O'Meara S, Galanville J. A rapid sys- tematic review of the clinical effectiveness and cost effectiveness of IDSA Guideline for Diabetic Foot Infections e CID 2012:54 (15 June) + el71 1ZOZ J9quiajdas gL uo jsanB Aq 696SSh/ZE19/Z1/+9/2/PN1e/p10/uo09dno"o1u peoe//:sdyy oy papeojumog 30 302. 30: 304, 30: 306. 307. 308. 309. 31 311. 312. 313. 314, 315, 316. 317. 318. 319. 320. 321. 2 debriding agents in treating surgical wounds healing by secondary intention. NHS HTA Programme, the National Institute of Clinical Excellence, NHS Centre for Reviews and Dissemination: University of York, 2000:1-8. . Armstrong DG, Lavery LA, Vazquez JR, Nixon BP, Boulton AJ. How and why to surgically debride neuropathic diabetic foot wounds. ] Am Podiatr Med Assoc 2002; 92:402-4, Singhal A, Reis ED, Kerstein MD. Options for nonsurgical debride- ment of necrotic wounds. Adv Skin Wound Care 2001; 14:96-100; quiz 02-3. Attinger CE, Janis JE, Steinberg J, Schwartz J, Al-Attar A, Couch K. Clinical approach to wounds: debridement and wound bed prep- aration including the use of dressings and wound-healing adjuvants. Plast Reconstr Surg 2006; 117:725-1098. Attinger CE, Bulan E, Blume PA. Surgical debridement. The key to successful wound healing and reconstruction. Clin Podiatr Med Surg 2000; 17:599-630. Tantawi TI, Gohar YM, Kotb MM, Beshara FM, El-Naggar MM. Clinical and microbiological efficacy of MDT in the treatment of dia- betic foot ulcers. J Wound Care 2007; 16:379-83. Paul AG, Ahmad NW, Lee HL, et al. Maggot debridement therapy with Lucilia cuprina: a comparison with conventional debridement in diabetic foot ulcers. Int Wound ] 2009; 639-46. Lodge A, Jones M, Thomas S. Maggots 'n' chips: a novel approach to the treatment of diabetic ulcers. Br ] Community Nurs 2006; 11 (Suppl):23-6. Edwards J, Stapley S. Debridement of diabetic foot ulcers. Cochrane Database Syst Rev 2010; 4:CD003556. Sainsbury DC. Evaluation of the quality and cost-effectiveness of Versajet hydrosurgery. Int Wound J 2009; 624-9. Caputo WJ, Beggs DJ, DeFede JL, Simm L, Dharma H. A prospective randomised controlled clinical trial comparing hydrosurgery debride- ment with conventional surgical debridement in lower extremity ulcers. Int Wound ] 2008; 5:288-94. Cavanagh PR. Therapeutic footwear for people with diabetes. Dia- betes Metab Res Rev 2004; 20(Suppl 1):551-5. Mueller MJ, Diamond JE, Sinacore DR, et al. Total contact casting in treatment of diabetic plantar ulcers. Controlled clinical trial. Diabetes Care 1989; 12:384-8. Bus SA, Valk GD, van Deursen RW, et al. The effectiveness of foot- wear and ofíloading interventions to prevent and heal foot ulcers and reduce plantar pressure in diabetes: a systematic review. Diabetes Metab Res Rev 2008; 24(Suppl 1):5162-80. Katz 1A, Harlan A, Miranda-Palma B, et al. A randomized trial of two irremovable offloading devices in the management of plantar neuropathic diabetic foot ulcers. Diabetes Care 2005; 28:555-9. Nabuurs-Franssen MH, Sleegers R, Huijberts MS, et al. Total contact casting of the diabetic foot in daily practice: a prospective follow-up study. Diabetes Care 2005; 28:243-7. Frykberg RG, Zgonis T, Armstrong DG, et al. Diabetic foot disorders. A clinical practice guideline (2006 revision). J Foot Ankle Surg 2006; 4551-66. Cavanagh PR, Lipsky BA, Bradbury AW, Botek G. Treatment for dia- betic foot ulcers. Lancet 2005; 366:1725-35. Spencer S. Pressure relieving interventions for preventing and treating diabetic foot ulcers. Cochrane Database Syst Rev 2000; 3:CD002302. Cardinal M, Eisenbud DE, Phillips T, Harding K. Early healing rates and wound area measurements are reliable predictors of later com- plete wound closure. Wound Repair Regen 2008; 16:19-22. Ince P, Game EL, Jefícoate W]. Rate of healing of neuropathic ulcers of the foot in diabetes and its relationship to ulcer duration and ulcer area. Diabetes Care 2007; 30:660-3. Chuck AW, Hailey D, Jacobs P, Perry DC. Cost-effectiveness and budget impact of adjunctive hyperbaric oxygen therapy for diabetic foot ulcers. Int J Technol Assess Health Care 2008; 24:178-83. 322. 323. 324, 32 326. 327. 328. 329. 330. 33 332. 333. 334, 335, 336. 337. 338. 339, 340. 341. Goldman RJ. Hyperbaric oxygen therapy for wound healing and limb salvage: a systematic review. PM R 2009; 1:471-89. Kranke P, Bennett M, Roeckl-Wiedmann Í, Debus S. Hyperbaric oxygen therapy for chronic wounds. Cochrane Database Syst Rev 2004; 2:C.D004123. Lipsky BA, Berendt AR. Hyperbaric oxygen therapy for diabetic foot wounds: has hope hurdled hype? Diabetes Care 2010; 33:1143-5. .. Wieman T], Smiell JM, Su Y. Efficacy and safety of a topical gel for- mulation of recombinant human platelet-derived growth factor-BB (becaplermin) in patients with chronic neuropathic diabetic ulcers. A phase III randomized placebo-controlled double-blind study. Dia- betes Care 1998; 21:822-7. Robson M. Integrating the results of phase IV (postmarketing) clini- cal trial with four previous trials reinforces the position of Regranex (becaplermin) gel 0.01% is an effective adjunct to the treatment of diabetic foot ulcer. J Appl Res 2005; 5:35-45. Viswanathan V, Mahesh U, Jayaraman M, Shina K, Ramachandram A. Beneficial role of granulocyte colony stimulating factor in foot infection in diabetic patients. J Assoc Physicians India 2003; 51:90-1. Gough A, Clapperton M, Rolando N, Foster AV, Philpott-Howard J, Edmonds ME. Randomised placebo-controlled trial of granulocyte- colony stimulating factor in diabetic foot infection. Lancet 1997; 350:855-9. de Lalla E, Pellizzer G, Strazzabosco M, et al. Randomized prospec- tive controlled trial of recombinant granulocyte colony-stimulating factor as adjunctive therapy for limb-threatening diabetic foot infec- tion. Antimicrob Agents Chemother 2001; 45:1094-8. Yonem A, Cakir B, Guler S, Azal OO, Corakci A. Effects of granulo- cyte-colony stimulating factor in the treatment of diabetic foot infec- tion. Diabetes Obes Metab 2001; 3:332-7. . Kastenbauer T, Hornlein B, Sokol G, Irsigler K. Evaluation of gra- nulocyte-colony stimulating factor (Filgrastim) in infected diabetic foot ulcers. Diabetología 2003; 4627-30. Huang P, Li S, Han M, Xiao Z, Yang R, Han ZC. Autologous trans- plantation of granulocyte colony-stimulating factor-mobilized per- ipheral blood mononuclear cells improves critical limb ischemia in diabetes. Diabetes Care 2005; 28:2155-60. Cruciani M, Lipsky BA, Mengoli C, de Lalla E. Granulocyte-colony stimulating factors as adjunctive therapy for diabetic foot infections. Cochrane Database Syst Rev 2009; 3:CD006810. Gentzkow GD, Iwasaki SD, Hershon KS, et al. Use of dermagraft, a cultured human dermis, to treat diabetic foot ulcers. Diabetes Care 1996; 19:350-4. Naughton G, Mansbridge J, Gentzkow G. A metabolically active human dermal replacement for the treatment of diabetic foot ulcers. Artif Organs 1997; 21:1203-10. Marston WA, Hanft J, Norwood P, Pollak R. The efficacy and safety of Dermagraft in improving the healing of chronic diabetic foot ulcers: results ofa prospective randomized trial. Diabetes Care 2003; 26:1701-5. Blume PA, Walters J, Payne W, Ayala J, Lantis J. Comparison of negative pressure wound therapy using vacuum-assisted closure with advanced moist wound therapy in the treatment of diabetic foot ulcers: a multicenter randomized controlled trial. Diabetes Care 2008; 31:631-6. Armstrong DG, Lavery LA. Negative pressure wound therapy after partial diabetic foot amputation: a multicentre, randomised con- trolled trial. Lancet 2005; 366:1704-10. Wu SC, Marston W, Armstrong DG. Wound care: the role of ad- vanced wound-healing technologies. ] Am Podiatr Med Assoc 2010; 100:385-94. Gregor S, Maegele M, Sauerland S, Krahn JE, Peinemann E, Lange S. Negative pressure wound therapy: a vacuum of evidence? Arch Surg 2008; 143:189-96. Fincke BG, Miller DR, Turpin R. A classification of diabetic foot in- fections using ICD-9-CM codes: application to a large computerized medical database. BMC Health Serv Res 2010; 10:192. el72 » CID 2012:54 (15 June) e Lipsky et al 1ZOZ J9quiajdas gL uo jsanB Aq 696SSh/ZE19/Z1/+9/2/PN1e/p10/uo09dno"o1u peoe//:sdyy oy papeojumog 342. 343. Fincke BG, Miller DR, Christiansen CL, Turpin RS. Variation in anti- 344. Jefícoate WJ, Chipchase SY, Ince P, Game FL. Assessing the biotic treatment for diabetic patients with serious foot infections: a ret- outcome of the management of diabetic foot ulcers using ulcer- rospective observational study. BMC Health Serv Res 2010; 10: related and person-related measures. Diabetes Care 2006; 29: Sotto A, Richard JL, Combescure C, et al. Beneficial effects of imple- 17847. menting guidelines on microbiology and costs of infected diabetic 345. Kimsey DB. Lean methodology in health care. AORN ] 2010; foot ulcers. Diabetologia 2010; 53:2249-55. 92:53-60. IDSA Guideline for Diabetic Foot Infections e CID 2012:54 (15 June) + el73 1ZOZ J9quiajdas gL uo jsanB Aq 696SSh/ZE19/Z1/+9/2/PN1e/p10/uo09dno"o1u peoe//:sdyy oy papeojumog