IWGDF Guideline on Diabetic Foot Infection PDF

IWGDF Guideline on the diagnosis and treatment of foot infection in persons with diabetes Part of the 2019 IWGDF Guidelines on the Prevention and Management of Diabetic Foot Disease...

IWGDF Guideline on the diagnosis and treatment of foot infection in persons with diabetes Part of the 2019 IWGDF Guidelines on the Prevention and Management of Diabetic Foot Disease IWGDF Guidelines IWGDF Infection Guideline LIST OF RECOMMENDATIONS 1. a) Diagnose a soft tissue diabetic foot infection clinically, based on the presence of local or systemic signs and symptoms of inflammation. (Strength of recommendation: Strong; Quality of evidence: Low) b) Assess the severity of any diabetic foot infection using the Infectious Diseases Society of America/International Working Group on the Diabetic Foot classification scheme. (Strong, Moderate) 2. Consider hospitalizing all persons with diabetes and a severe foot infection, and those with a moderate infection that is complex or associated with key relevant morbidities. (Strong; Low) 3. In a person with diabetes and a possible foot infection for whom the clinical examination is equivocal or uninterpretable, consider ordering an inflammatory serum biomarker, such as C- reactive protein, erythrocyte sedimentation rate and perhaps procalcitonin, as an adjunctive measure for establishing the diagnosis. (Weak; Low) 4. As neither electronically measuring foot temperature nor using quantitative microbial analysis has been demonstrated to be useful as a method for diagnosing diabetic foot infection, we suggest not using them. (Weak; Low) 5. In a person with diabetes and suspected osteomyelitis of the foot, we recommend using a combination of the probe-to-bone test, the erythrocyte sedimentation rate (or C-reactive protein and/or procalcitonin), and plain X-rays as the initial studies to diagnose osteomyelitis. (Strong; Moderate) 6. a) In a person with diabetes and suspected osteomyelitis of the foot, if a plain X-ray and clinical and laboratory findings are most compatible with osteomyelitis, we recommend no further imaging of the foot to establish the diagnosis. (Strong; Low). b) If the diagnosis of osteomyelitis remains in doubt, consider ordering an advanced imaging study, such as magnetic resonance imaging scan, 18F-FDG- positron emission tomography/computed tomography (CT) or leukocyte scintigraphy (with or without CT). (Strong; Moderate) 7. In a person with diabetes and suspected osteomyelitis of the foot, in whom making a definitive diagnosis or determining the causative pathogen is necessary for selecting treatment, collect a sample of bone (percutaneously or surgically) to culture clinically relevant bone microorganisms and for histopathology (if possible). (Strong; Low) 8. a) Collect an appropriate specimen for culture for almost all clinically infected wounds to determine the causative pathogens. (Strong; Low) b) For a soft tissue diabetic foot infection, obtain a sample for culture by aseptically collecting a tissue specimen (by curettage or biopsy) from the ulcer. (Strong; Moderate) 9. Do not use molecular microbiology techniques (instead of conventional culture )for the first-line identification of pathogens from samples in a patient with a diabetic foot infection. (Strong; Low) 10. Treat a person with a diabetic foot infection with an antibiotic agent that has been shown to be effective in a published randomized controlled trial and is appropriate for the individual patient. Some agents to consider include: penicillins, cephalosporins, carbapenems, metronidazole (in combination with other antibiotic[s]), clindamycin, linezolid, daptomycin, fluoroquinolones, or vancomycin, but not tigecycline. (Strong; High) © 2019 The International Working Group on the Diabetic Foot IWGDF Guidelines IWGDF Infection Guideline 11. Select an antibiotic agent for treating a diabetic foot infection based on: the likely or proven causative pathogen(s) and their antibiotic susceptibilities; the clinical severity of the infection; published evidence of efficacy of the agent for diabetic foot infections; risk of adverse events, including collateral damage to the commensal flora; likelihood of drug interactions; agent availability; and, financial costs. (Strong; Moderate) 12. Administer antibiotic therapy initially by the parenteral route to any patient with a severe diabetic foot infection. Switch to oral therapy if the patient is clinically improving, has no contraindications to oral therapy and if there is an appropriate oral agent available. (Strong; Low) 13. Treat patients with a mild diabetic foot infection, and most with a moderate diabetic foot infection, with oral antibiotic therapy, either at presentation or when clearly improving with initial intravenous therapy. (Weak; Low) 14. We suggest not using any currently available topical antimicrobial agent for treating a mild diabetic foot infection. (Weak; Moderate) 15. a) Administer antibiotic therapy to a patient with a skin or soft tissue diabetic foot infection for a duration of 1 to 2 weeks. (Strong; High) b) Consider continuing treatment, perhaps for up to 3-4 weeks, if the infection is improving but is extensive, is resolving slower than expected, or if the patient has severe peripheral artery disease. (Weak; Low) c) If evidence of infection has not resolved after 4 weeks of apparently appropriate therapy, re- evaluate the patient and reconsider the need for further diagnostic studies or alternative treatments. (Strong; Low) 16. For patients who have not recently received antibiotic therapy and who reside in a temperate climate area, target empiric antibiotic therapy at just aerobic gram-positive pathogens (beta- hemolytic streptococci and Staphylococcus aureus) in cases of a mild diabetic foot infection. (Strong; Low) 17. For patients residing in a tropical/subtropical climate, or who have been treated with antibiotic therapy within a few weeks, have a severely ischemic affected limb, or a moderate or severe infection, we suggest selecting an empiric antibiotic regimen that covers gram-positive pathogens, commonly isolated gram-negative pathogens, and possibly obligate anaerobes in cases of moderate to severe diabetic foot infections. Then, reconsider the antibiotic regimen based on both the clinical response and culture and sensitivity results. (Weak; Low) 18. Empiric treatment aimed at Pseudomonas aeruginosa is not usually necessary in temperate climates, but consider it if P. aeruginosa has been isolated from cultures of the affected site within the previous few weeks or in tropical/subtropical climates (at least for moderate or severe infection). (Weak; Low) 19. Do not treat clinically uninfected foot ulcers with systemic or local antibiotic therapy with the goal of reducing the risk of infection or promoting ulcer healing. (Strong; Low) 20. Non-surgeons should urgently consult with a surgical specialist in cases of severe infection, or of moderate infection complicated by extensive gangrene, necrotizing infection, signs suggesting deep (below the fascia) abscess or compartment syndrome, or severe lower limb ischemia. (Strong; Low) © 2019 The International Working Group on the Diabetic Foot IWGDF Guidelines IWGDF Infection Guideline 21. a) In a patient with diabetes and uncomplicated forefoot osteomyelitis, for whom there is no other indication for surgical treatment, consider treating with antibiotic therapy without surgical resection of bone. (Strong; Moderate) b) In a patient with probable diabetic foot osteomyelitis with concomitant soft tissue infection, urgently evaluate for the need for surgery as well as intensive post-operative medical and surgical follow-up. (Strong; Moderate) 22. Select antibiotic agents for treating diabetic foot osteomyelitis from among those that have demonstrated efficacy for osteomyelitis in clinical studies. (Strong; Low) 23. a) Treat diabetic foot osteomyelitis with antibiotic therapy for no longer than 6 weeks. If the infection does not clinically improve within the first 2-4 weeks, reconsider the need for collecting a bone specimen for culture, undertaking surgical resection, or selecting an alternative antibiotic regimen. (Strong; Moderate) b) Treat diabetic foot osteomyelitis with antibiotic therapy for just a few days if there is no soft tissue infection and all the infected bone has been surgically removed. (Weak; Low) 24. For diabetic foot osteomyelitis cases that initially require parenteral therapy, consider switching to an oral antibiotic regimen that has high bioavailability after perhaps 5-7 days, if the likely or proven pathogens are susceptible to an available oral agent and the patient has no clinical condition precluding oral therapy. (Weak; Moderate) 25. a) During surgery to resect bone for diabetic foot osteomyelitis, consider obtaining a specimen of bone for culture (and, if possible, histopathology) at the stump of the resected bone to identify if there is residual bone infection. (Weak; Moderate) b) If an aseptically collected culture specimen obtained during the surgery grows pathogen(s), or if the histology demonstrates osteomyelitis, administer appropriate antibiotic therapy for up to 6 weeks. (Strong; Moderate) 26. For a diabetic foot infection do not use hyperbaric oxygen therapy or topical oxygen therapy as an adjunctive treatment if the only indication is specifically for treating the infection. (Weak; Low) 27. To specifically address infection in a diabetic foot ulcer: a) do not use adjunctive granulocyte colony stimulating factor treatment (Weak; Moderate) and, b) do not routinely use topical antiseptics, silver preparations, honey, bacteriophage therapy, or negative-pressure wound therapy (with or without instillation). (Weak; Low) © 2019 The International Working Group on the Diabetic Foot IWGDF Guidelines IWGDF Infection Guideline INTRODUCTION The prevalence of diabetes continues to increase worldwide, leading to a rising incidence of foot complications, including infections.1 Diabetic foot infections (DFIs) are associated with substantial morbidities, requiring frequent healthcare provider visits, daily wound care, antimicrobial therapy, surgical procedures, with associated high health care costs.2,3 Of particular importance, DFIs remain the most frequent diabetic complication requiring hospitalization and the most common precipitating event leading to lower extremity amputation.4-6 Outcomes in patients presenting with an infected diabetic foot ulcer are poor: in one large prospective study at the end of one year the ulcer had healed in only 46% (and it later recurred in 10% of these), while 15% had died and 17% required a lower extremity amputation.5 Thus, it is not surprising that a bibliographic analysis of global research on diabetic foot ulcers in the past 10 years found that infection (DFI) scored among the most frequent topics and the most highly cited publications.7 Managing DFIs requires careful attention to properly diagnosing the condition, obtaining appropriate specimens for culture, thoughtfully selecting antimicrobial therapy, quickly determining when surgical interventions are required and providing any needed additional wound and overall patient care. A systematic, evidence-based approach to managing DFIs likely improves outcomes, specifically resolution of infection and avoidance of complications, such as lower extremity amputation. This is best delivered by interdisciplinary teams, which should include among the membership, whenever possible, an infectious diseases or clinical/medical microbiology specialist.8 This team should, of course, also attempt to ensure optimal local wound care (e.g., cleansing and debridement), pressure off-loading, vascular assessment and treatment if needed, and metabolic (particularly glycemic) control. Several guidelines are available to assist clinicians in managing DFIs. A panel of infectious diseases experts convened by the International Working Group on the Diabetic Foot (IWGDF) has published widely used guideline documents quadrennially since 2004.9 This current guideline updates both the format and content of the most recent previous guideline, published in 2016. 9 Specifically, it incorporates information from the concurrently published systematic reviews of the literature developed by the infection committee: an update of the 2016 systematic review on interventions in the management of infection in the diabetic foot 10 and a newly conducted review of issues related to diagnosis of DFIs. Of note, we have slightly modified the classification system for defining the presence and severity of an infection of the foot in a person with diabetes (see Table 1) that the IWGDF and the Infectious Diseases Society of America (IDSA) first developed in 2004.11,12 In this guideline we have broadly divided our recommendations into those related to diagnosis, microbiologic assessment, and treatment (antibiotic, surgical, adjunctive). © 2019 The International Working Group on the Diabetic Foot IWGDF Guidelines IWGDF Infection Guideline BACKGROUND Infection is best defined as an invasion and multiplication of microorganisms in host tissues that induces a host inflammatory response, usually followed by tissue destruction. Almost all DFIs occur in open wounds; as these are colonized with microorganisms, infection cannot be defined using only the results of wound cultures. Instead, DFI is defined clinically as the presence of manifestations of an inflammatory process in any tissue below the malleoli in a person with diabetes mellitus. In persons with diabetic foot complications, signs and symptoms of inflammation may, however, be masked by the presence of peripheral neuropathy or peripheral artery disease or immune dysfunction. DFIs usually begin with a break in the protective cutaneous envelope, typically in a site of trauma or ulceration, most often in a person with peripheral neuropathy and frequently with peripheral artery disease.13 While rarely the primary cause of foot ulcers, the presence of limb ischemia increases the risk of an ulcer becoming infected,4,14-16 and adversely affects the outcome of infection.4,17,18 Foot ulcers in persons with diabetes often become chronic, related to increased biomechanical stress, hyperglycemia and its metabolic consequences, persistent inflammation, apoptosis and ischemia.19,20 Factors that predispose to foot infection include having: an ulcer that is deep, long-standing or recurrent, or of traumatic etiology; ill- defined diabetes-related immunological perturbations, particularly with neutrophil dysfunction; or, chronic renal failure.14,16,21-24 Although examined in only a few studies, a history of chronic hyperglycemia may predispose to DFIs and its presence at presentation may suggest a rapidly progressive or destructive (necrotizing) infection.25,26 While most DFIs are relatively superficial at presentation, microorganisms can spread contiguously to subcutaneous tissues, including fascia, tendons, muscles, joints and bones. The anatomy of the foot, which is divided into several separate but intercommunicating compartments, fosters proximal spread of infection.27 The inflammatory response induced by infection may cause compartmental pressure to exceed capillary pressure, leading to ischemic tissue necrosis and thereby progressive infection.28,29 The tendons within the compartments facilitate proximal spread of infection, which usually moves from higher to lower pressure areas. Bacterial virulence factors may also play a role in these complex infections.30,31 Systemic symptoms (e.g., feverishness, chills), marked leukocytosis or major metabolic disturbances are uncommon in patients with a DFI, but their presence denotes a more severe, potentially limb- threatening (or even life-threatening) infection.4,32,33 If not diagnosed and properly treated, DFIs tend to progress, sometimes rapidly.34 Thus, an experienced consultant (or team) should optimally evaluate a patient with a severe DFI within 24 hours.35 Accumulations of purulent secretions, especially if under pressure or associated with necrosis, require prompt (usually within 24 hours) decompression and drainage. Although bone resection (preferably limited, avoiding amputation) is often useful for treating osteomyelitis, it is usually soft tissue infection that requires urgent antimicrobial therapy and surgical intervention. The aim of this document is to provide guidelines for the diagnosis and treatment of foot infections in people with diabetes. These are intended to be of practical use for treating clinicians, based on all available scientific evidence. © 2019 The International Working Group on the Diabetic Foot IWGDF Guidelines IWGDF Infection Guideline METHODS In this guideline we have followed the GRADE methodology, which is structured around clinical questions in the PICO-format (Patient-Intervention-Comparison-Outcome), systematic searches and assessment of the available evidence, followed by developing recommendations and their rationale.36,37 First, a multidisciplinary working group of independent experts (the authors of this guideline) was installed by the IWGDF editorial board. The members of the working group devised the clinical questions, which were revised after consultation with external experts from various geographical regions and the IWGDF Editorial Board. The aim was to ensure the relevance of the questions for clinicians and other health care professionals in providing useful information on the management of foot infections in persons with diabetes. We also formulated what we considered critically important outcomes relevant for daily care, using the set of outcomes defined by Jeffcoate et al.38 as a reference guide. Second, we systematically reviewed the literature to address the agreed upon clinical questions. For each assessable outcome we graded the quality of evidence based on the risk of bias of included studies, effect sizes, presence of inconsistency, and evidence of publication bias (the latter where appropriate). We then rated the quality of evidence as ‘high’, ‘moderate’ or ‘low’. The systematic reviews supporting this guideline are published separately.39,40 Third, we formulated recommendations to address each clinical question. We aimed to be clear, specific and unambiguous on what we recommend, for which persons, and under what circumstances. Using the GRADE system we provided the rationale for how we arrived at each recommendation, based on the evidence from our systematic reviews 39,40, expert opinion where evidence was not available, and a careful weighing of the benefits and harms, patient preferences, and financial costs (resource utilization) related to the intervention or diagnostic method 36,37. Based on these factors, we graded the strength of each recommendation as ‘strong’ or ‘weak’, and for or against a particular intervention or diagnostic method. All our recommendations (with their rationales) were reviewed by the same international experts who reviewed the clinical questions, as well as by the members of the IWGDF Editorial Board. We refer those seeking a more detailed description on the methods for developing and writing these guidelines to the ‘IWGDF Guidelines development and methodology’ document.41 DIAGNOSIS PICO 1a: In a person with diabetes and a foot infection, do increasing levels of severity of the IWGDF/IDSA criteria correlate with increasing rates of adverse outcomes (e.g., need for hospitalization, failure to resolve infection, lower extremity amputation)? Recommendation 1: a) Diagnose a soft tissue diabetic foot infection clinically, based on the presence of local or systemic signs and symptoms of inflammation. (Strong; Low) b) Assess the severity of any diabetic foot infection using the Infectious Diseases Society of America/International Working Group on the Diabetic Foot classification scheme. (Strong, Moderate) © 2019 The International Working Group on the Diabetic Foot IWGDF Guidelines IWGDF Infection Guideline Rationale: The clinician seeing a patient with a diabetic foot ulcer should always assess for the presence of an infection and, if present, classify the infection’s severity. Experts have proposed many classification schemes for diabetic foot ulcers (see IWGDF guideline on classification in this issue), many of which only include the presence of absence of “infection” (which is rarely specifically defined), but in the past decade most authorities have recommended using the IWGDF/IDSA classification that was first published in 2004. Two prospective cohort studies have validated all or part of the IWGDF/IDSA DFI classification, and one prospective and four retrospective cohort studies have validated the IWGDF/IDSA as part of a larger diabetic foot classification system. These and other studies from around the world have provided some evidence that increasing severity of infection is associated with higher levels of inflammatory markers,42 a greater likelihood of the patient being hospitalized for treatment, longer duration of hospital stay, greater likelihood and higher level of lower extremity amputation, and higher rate of readmission.4,33,43,44 Sepsis is uncommonly reported (perhaps partly being unrecognized) in patients with a DFI, even in the presence of extensive local signs and symptoms of infection. Thus, we considered whether we should replace using the findings of the systemic inflammatory response syndrome (SIRS) by another classification for severe infection, e.g., national early warning score (NEWS),45,46 or quick sequential organ failure assessment (qSOFA).47 These were, however, developed for identification or prediction of outcomes in patients with sepsis and there are no data to support changing from using SIRS to other classifications for DFIs. Two commonly used classifications for diabetic foot ulcers, WIfI (wound, ischemia, foot infection) and SINBAD (site, ischemia, neuropathy, bacterial Infection, and depth), which use the IWGDF/IDSA classification for the infection component, have been validated with patient data.48,49 The IWGDF/IDSA classification has several advantages, including having the most studies to validate its use in different populations. It is relatively easy for the clinician to use, requiring only a clinical examination and standard blood and imaging tests, helps direct diagnostic and therapeutic decisions about infection, has no obvious harms and has been widely accepted by the academic community and practicing clinicians. Furthermore, other available classification schemes were not specifically developed or validated for DFIs.50 For the current guideline we have made a clarification in the infection classification scheme (Table 1). We define infection based on the presence of evidence of: 1) inflammation of any part of the foot, not just an ulcer or wound; or, 2) findings of the systemic inflammatory response. We have also made one change in the classification scheme. Because of the important diagnostic, therapeutic and prognostic implications of osteomyelitis, we now separate it out by indicating the presence of bone infection with” (O)” after the grade number (3 or 4) (see Table 1). Although uncommon, bone infection may be documented in the absence of local inflammatory findings. In this case, the foot should be classified as infected (either grade 3/moderate if there are no SIRS findings or 4/severe if there are), with an (O). As the presence of osteomyelitis means the foot is infected it cannot be grade 1/uninfected, and because the infection is subcutaneous it cannot be grade 2/mild. As the grade 3 (moderate) classification is the largest and most heterogeneous group, we considered dividing it into subgroups of just lateral spread (≥2 cm from the wound margin), or just vertical spread (deeper than the subcutaneous tissue). We discarded this idea as it would add to the complexity of the diagnostic scheme, especially with our decision to add the (O) for osteomyelitis. © 2019 The International Working Group on the Diabetic Foot IWGDF Guidelines IWGDF Infection Guideline Table 1. The classification system for defining the presence and severity of an infection of the foot in a person with diabetes Clinical classification of infection, with definitions IWGDF classification Uninfected No systemic or local symptoms or signs of infection 1 (uninfected) Infected At least two of these items are present: § Local swelling or induration § Erythema >0.5 cm* around the wound § Local tenderness or pain § Local increased warmth § Purulent discharge And no other cause(s) of an inflammatory response of the skin (e.g. trauma, gout, acute Charcot neuro-osteoarthropathy, fracture, thrombosis or venous stasis) Infection with no systemic manifestations (see below) involving 2 (mild infection) § only the skin or subcutaneous tissue (not any deeper tissues), and § any erythema present does not extend >2 cm** around the wound Infection with no systemic manifestations, and involving: 3 (moderate infection) § erythema extending ≥2 cm* from the wound margin, and/or § tissue deeper than skin and subcutaneous tissues (e.g. tendon, muscle, joint, bone,) Any foot infection with associated systemic manifestations (of the 4 (severe infection) systemic inflammatory response syndrome [SIRS]), as manifested by ≥2 of the following: § Temperature >38 °C or 90 beats/minute § Respiratory rate >20 breaths/minute or PaCO2 12,000/mm3, or 10% immature (band) forms Infection involving bone (osteomyelitis) Add “(O)” after 3 or 4*** Note: * Infection refers to any part of the foot, not just of a wound or an ulcer; ** In any direction, from the rim of the wound. The presence of clinically significant foot ischemia makes both diagnosis and treatment of infection considerably more difficult; *** If osteomyelitis is demonstrated in the absence of ≥2 signs/symptoms of local or systemic inflammation, classify the foot as either grade 3(O) (if 2 cm), distant from ulceration or rapidly progressive (including lymphangitis) Local signs/symptoms Severe inflammation or induration, crepitus, bullae, discoloration, necrosis or gangrene, ecchymoses or petechiae and new anesthesia or localized pain General Presentation Acute onset/worsening or rapidly progressive Systemic signs Fever, chills, hypotension, confusion and volume depletion Laboratory tests Leukocytosis, highly elevated C-reactive protein or erythrocyte sedimentation rate, severe or worsening hyperglycemia, acidosis, new/worsening azotemia and electrolyte abnormalities Complicating features Presence of a foreign body (accidentally or surgically implanted), puncture wound, deep abscess, arterial or venous insufficiency, lymphedema, immunosuppressive illness or treatment, acute kidney injury Failing treatment Progression while on apparently appropriate antibiotic and supportive therapy B – Some Factors suggesting hospitalization may be necessary Severe infection (see findings suggesting a more serious diabetic foot infection above) Metabolic or hemodynamic instability Intravenous therapy needed (and not available/appropriate as an outpatient) Diagnostic tests needed that are not available as an outpatient Foot ischemia is present Surgical procedures (more than minor) required Failure of outpatient management Patient unable or unwilling to comply with outpatient-based treatment Need for more complex dressing changes than patient/caregivers can provide Need for careful, continuous observation PICO 2a: In a person with diabetes and a suspected foot infection, how well do the IWGDF/IDSA clinical criteria for diagnosing soft tissue infection correlate with other diagnostic tests? Recommendation 3: In a person with diabetes and a possible foot infection for whom the clinical examination is equivocal or uninterpretable, consider ordering an inflammatory serum biomarker, such as C-reactive protein, erythrocyte sedimentation rate and perhaps procalcitonin, as an adjunctive measure for establishing the diagnosis. (Weak; Low) Rationale: There are several diagnostic methods against which clinical examinations could be compared to evaluate their ability to assess the presence or severity of foot infection, or to differentiate soft tissue © 2019 The International Working Group on the Diabetic Foot IWGDF Guidelines IWGDF Infection Guideline from bone infection. Most available studies assessed the value of blood tests, especially white blood cell counts (WBC), erythrocyte sedimentation rate (ESR), C-reactive protein (CRP) and procalcitonin (PCT), by comparing them to results of IDSA/IWGDF criteria for infection.9,42,54. Unfortunately, the severity of infection in patients included in the available studies was not always clearly defined, which may account for interstudy differences in findings. In addition, many studies do not specify if enrolled patients were recently treated with antibiotic therapy, which could affect results. Of particular note is the WBC level, as it is used as part of the IDSA/IWGDF criteria for classifying infection as severe/grade 4. The available studies55-58 found little correlation with infection severity, with about half of the patients diagnosed with a DFI having a normal WBC.59,60 In most studies ESR values have been higher in patients with an infected diabetic foot ulcer (IDFU) compared with a noninfected DFU (NIDU).55,56 ESR values can be affected by various co-morbidities (e.g., anemia, azotemia) and may not be elevated in acute infections, due to the relatively slow response of this inflammatory biomarker, but a highly elevated ESR (≥70 mm/h) is more common in patients with bone than with just soft tissue infections. Most studies of serum PCT levels have also found that levels were significantly higher in IDFU than NIDFU, but there was little correlation between the values and the infection severity. Furthermore, PCT has, until recently in some areas, been costlier than CRP, and it may be unavailable in many clinical laboratories. Compared to ESR, CRP levels tend to rise more quickly with infection and fall more quickly with resolution of infection. Serum values of CRP55,56,61 have consistently been found to be significantly higher in IDFU than in NIDFU, and higher in patients with NIDFU than in those with no foot ulcer, with levels increasing significantly with the severity of infection.56,62 Overall, CRP and PCT have shown higher diagnostic accuracy than WBC or ESR. Some studies have investigated using various combinations of these inflammatory markers, but none seemed especially useful and the highly variable cut off values make the results difficult to interpret. Serum tests for these common biomarkers are widely available, easily obtained, and most are relatively inexpensive. A few studies investigated other inflammatory markers for their role in diagnosing or following DFIs, but they were small and of low quality.42 PICO 2b: In a person with diabetes and a suspected foot infection, do the IDSA/IWGDF criteria for diagnosing soft tissue infection correlate with results of skin temperature measurement or quantitative microbiology? Recommendation 4: As neither electronically measuring foot temperature nor using quantitative microbial analysis has been demonstrated to be useful as a method for diagnosing diabetic foot infection, we suggest not using them. (Weak; Low) Rationale: While various imaging tests are widely used for diagnosing bone infection (see PICO D3 below), there are few data on their usefulness for soft tissue infections. Other diagnostic tests studied for assessing DFI include photographic foot imaging and infrared thermography. Several studies with these instruments have examined their value in predicting foot ulcerations. A few studies have demonstrated that an increase in temperature in one area on the foot, and perhaps various © 2019 The International Working Group on the Diabetic Foot IWGDF Guidelines IWGDF Infection Guideline photographic assessments, have a relatively weak correlation with clinical evidence of infection on examination.63-66 Overall, employing either infrared or digital thermography does not appear to provide substantial help in diagnosing infection or predicting clinical outcome in patients with a DFU seen in the hospital setting. While infrared imaging likely has no harms, it is limited by low availability. It is possible that it may be of value when coupled to photographic assessment through telemedicine in the early diagnosis of DFI. Some advocate using the presence of high numbers of bacteria on culture (usually defined as ≥105 colony-forming units per gram of tissue) as a basis for differentiating infected from uninfected DFUs.67,68 However, there is no convincing data (from conventional culture or molecular methods) supporting this concept.69 In the studies that assessed the validity of clinical signs for the diagnosis of DFI using microbial analysis as a referent test, the criteria used to define infection varied among the authors and even between studies conducted by the same team. In some microbial analysis studies, patients receiving antibiotics at the time of the wound sampling (which may cause diminished organism counts) were included, while others failed to provide information on this important confounding issue. Of note, these methods of measuring what is sometimes called “wound bioburden” are time-consuming and relatively expensive. Furthermore, neither quantitative classical culture nor molecular microbiological techniques are currently available for most clinicians in their routine practice. PICO 3: In a person with diabetes and suspected bone infection of the foot, which diagnostic tests best correlate with the presence of osteomyelitis, as diagnosed based on culture and/or histopathology of a bone specimen? Recommendation 5: In a person with diabetes and suspected osteomyelitis of the foot, we recommend using a combination of the probe-to-bone test, the erythrocyte sedimentation rate (or C-reactive protein and/or procalcitonin), and plain X-rays as the initial studies to diagnose osteomyelitis. (Strong; Moderate) Rationale: Diagnosing osteomyelitis in the diabetic foot may be difficult, partly because of a lack of a universally accepted definition or criterion standard, and partly related to low levels of inter-test agreement among commonly used diagnostic tests.70 Osteomyelitis may be present underlying any DFU, especially those that have been present for many weeks or that are wide, deep, located over a bony prominence, showing visible bone or accompanied by an erythematous, swollen (“sausage”) toe.71,72 Among clinical examinations, the probe-to-bone (PTB) test is the most useful, but the performing clinician’s technique and experience, the ulcer’s location and its etiology may affect the test’s reliability.73,74 A systematic review of the PTB test found that for detecting DFO the sensitivity was 0.87 and specificity 0.83.75 Overall, in diagnosing DFO the PTB test suggests the diagnosis if it is positive in a high risk patient and helps rule it out if it is negative in a low risk patient. The procedure is easy to learn and perform, requiring only a sterile blunt metal probe (gently inserted into the wound, with a positive test defined by feeling a hard, gritty structure),76 is inexpensive and essentially harmless, but interobserver agreement is only moderate. Among blood tests, the ESR is the most useful, with a highly elevated rate (>70 mm/hr) suggesting bone infection.57,77 Any patient with possible bone infection should initially have plain x-rays of the foot. © 2019 The International Working Group on the Diabetic Foot IWGDF Guidelines IWGDF Infection Guideline Interpreted by an experienced reader, characteristic findings of bone infection (see Table 2) are highly suggestive of osteomyelitis, but x-rays are often negative in the first few weeks of infection and abnormal findings can be caused by Charcot osteoarthropathy and other disorders. Plain x-rays are widely available, relatively inexpensive and associated with minimal harm. A retrospective study of 107 patients with histologically proven DFO found that after adjusting for confounders, the WBC was not useful for diagnosing DFO, but ESR (in particular), as well as CRP and plain radiographs, were actually more useful than MRI.78 Recommendation 6: a) In a person with diabetes and suspected osteomyelitis of the foot, if a plain X-ray and clinical and laboratory findings are most compatible with osteomyelitis, we recommend no further imaging of the foot to establish the diagnosis. (Strong; Low). b) If the diagnosis of osteomyelitis remains in doubt, consider ordering an advanced imaging study, such as magnetic resonance imaging scan, 18F-FDG- positron emission tomography/computed tomography (CT) or leukocyte scintigraphy (with or without CT). (Strong; Moderate) Rationale: Depending on the patient setting, advanced imaging for diagnosing osteomyelitis is not needed in many patients. When needed, magnetic resonance imaging (MRI), with a sensitivity of about 0.9 and specificity of about 0.8, has been the most widely used test for decades.79 One retrospective study of 32 cases of pathologically proven DFO found that, compared to plain X-rays, MRI had added value in guiding surgical treatment in 65%, and a five times higher agreement with surgical findings.80 MRI is widely available (in high income countries), with lower costs than some of the newer advanced imaging technologies, and gives an overview of the presence and anatomy of both soft tissue and bone infections in the foot. The presence of reactive bone marrow edema from non-infectious pathologies, such as trauma, previous foot surgery or Charcot neuroarthropathy, lowers the specificity and positive predictive value.81,82 In selected patients with possible neuro-osteoarthropathy, newer techniques such as MR angiography, dynamic contrast-enhanced MRI or neurography may better distinguish Charcot from osteomyelitis.83-86 Newer advanced imaging tests, especially 18F-fluorodeoxyglucose (FDG)-PET/CT and 99mTc- exametazime (HMPAO)-labeled leukocyte scintigraphy can be used in patients with a contraindication to MRI, and appear to have a higher specificity than MRI (especially when noninfectious bony changes are more likely), but are limited in availability, require special expertise and are more expensive.87,88 Compared to other nuclear medicine techniques (e.g., leukocyte imaging), PET (especially with CT) offers high spatial resolution and precise anatomic localization, possibly higher sensitivity for chronic infection, easier performance, faster results, and low radiation exposure. However, currently supportive data for PET are less robust and it is less able to differentiate infection from inflammation (including from acute Charcot foot).89,90 The availability and cost of these advanced imaging techniques may vary in different locations, but they might be useful in situations when the diagnosis remains in doubt and there are limited options to obtain a bone biopsy. Advanced imaging (especially MRI) is also useful for surgical planning in selected cases, such as to identify purulent collections or the extent of bone involvement pre-operatively. As with soft tissue infections (see above), it may be difficult to know when DFO has been successfully treated. There are often few clinical signs and symptoms, although resolution of overlying soft tissue infection is reassuring. A decrease in previously elevated serum inflammatory markers suggests improving infection. Plain x-rays showing no further bone destruction, and better yet signs of bone healing, also © 2019 The International Working Group on the Diabetic Foot IWGDF Guidelines IWGDF Infection Guideline suggest improvement. And, some of the newer advanced imaging studies, e.g., WBC-labelled SPECT/CT, FDG PET/CT, may be more sensitive in demonstrating resolution of infection. The current state of the art, however, is that DFO is at best in “remission” if diagnostic tests suggest improvement, but should probably not be considered “cured" until there has been no evidence of recurrence for at least a year after the end of treatment.91,92 An additional outcome in patients treated for DFI is recurrence of the infection at the same location. In one study of over 1000 episodes of moderate or severe DFI (including osteomyelitis), recurrent infection was noted in 25% of patients within three years. Risk of recurrence was higher in those with type 1 diabetes, immunosuppression, a sequestrum, who did not undergo amputation or revascularization, but was unrelated to the route or duration of antibiotic therapy.91 Recommendation 7: In a person with diabetes and suspected osteomyelitis of the foot, in whom making a definitive diagnosis or determining the causative pathogen is necessary for selecting treatment, collect a sample of bone (percutaneously or surgically) to culture clinically relevant bone microorganisms and for histopathology (if possible). (Strong; Low) Rationale: Obtaining a specimen of bone to diagnose osteomyelitis of the diabetic foot is the generally accepted criterion standard for diagnosing the infection and the only definitive way to determine the causative pathogen. Available evidence suggests that collecting a bone specimen in an aseptic manner (i.e., percutaneously or per-operative, not through the wound), is safe and provides the most accurate assessment of true pathogens.93-96 A prospective direct comparison of 46 paired per-wound and transcutaneous bone biopsies in patients with suspected DFO found that results were identical in only 42%.97 To avoid a false-negative culture, some experts suggest delaying bone biopsy in a patient receiving antibiotics until they have been off therapy for at least a few days, and ideally for at least two weeks 93,94. While this seems theoretically sensible, reports from studies of various types of bone infection,98-101 including DFO,102 suggest that having receiving antibiotic therapy before a bone culture does not appear to reduce the percentage of positive cultures or time to culture positivity. Biopsy is generally not painful (as the majority of affected patients have sensory neuropathy) and complications are very rare.103 While it would be theoretically useful to obtain a bone specimen in almost all cases, this is often impractical as the procedure requires some time, experience and expense. Thus, it is most important to perform bone biopsy when it is difficult to guess the causative pathogen or its antibiotic susceptibility, e.g., in patients at risk for antibiotic-resistant isolates, who have been previously treated with antibiotics or who have had a soft tissue sample that grew multiple pathogens. Biopsy may not be needed if an aseptically collected deep tissue specimen from a soft tissue infection grows only a single virulent pathogen, especially S. aureus.93,94 The diagnosis of osteomyelitis is most assured if one or more bone specimens has both a positive culture and characteristic histopathological findings.104 Culture has the advantage of determining the causative pathogen, but histology may be more sensitive if the patient is on antibiotic therapy and more specific if specimen contamination is a concern. Of note, the inter- rater agreement on the diagnosis of osteomyelitis by histopathology is low (