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Medical therapy of diabetic foot infections

      Diabetic foot infections are a common and often serious problem, accounting for a greater number of hospital bed days than any other complication of diabetes. Despite advances in both antibiotic therapy and surgical management, these infections continue to be a major risk factor for amputations of the lower extremity. Although a number of wound size and depth classification systems have been adapted for use in codifying diabetic foot ulcerations, none are specific for infection. In 2003, the International Working Group on the Diabetic Foot developed guidelines for managing diabetic foot infections, including the first severity scale specific for these infections. The following year, the Infectious Diseases Society of America (IDSA) published their Diabetic Foot Infection Guidelines. In this article, we review some of the critical points from the Executive Summary of the IDSA document and provide a commentary following each issue to update the reader on any pertinent changes that have occurred since the publication of the original document in 2004. The importance of a multidisciplinary limb salvage team, apropos this special joint issue of the American Podiatric Medical Association and the Society for Vascular Surgery, cannot be overstated.
      Until 20 years ago, what little literature there was available on treating infections of the foot in persons with diabetes suggested that: almost all were polymicrobial; gram-negative bacilli and obligate anaerobes were frequent pathogens; virtually all such patients needed to be hospitalized; and they should be treated with parenteral, broad-spectrum antibiotic therapy. Studies published since 1990 have demonstrated that most of these assertions were at least exaggerations, if not myths. With the accumulating case series and investigations on treatment of diabetic foot infections (DFIs), especially randomized clinical trials and carefully conducted microbiological studies, by the early 2000s, it was time for convening experts in the field to develop evidence-based guidelines on diagnosing and treating DFIs.
      In 2003, the International Working Group on the Diabetic Foot (IWGDF) appointed a committee that drafted DFI guidelines
      • Lipsky B.A.
      A report from the international consensus on diagnosing and treating the infected diabetic foot.
      that were approved by members from over 60 participating countries and subsequently published and distributed in multiple languages on DVD (www.iwgdf.org). The following year, the Infectious Diseases Society of America (IDSA) empanelled an expert committee to draft diabetic foot infection clinical guidelines that were published in 2004.
      • Lipsky B.A.
      • Berendt A.R.
      • Deery H.G.
      • Embil J.
      • Joseph W.S.
      • Karchmer A.W.
      • et al.
      Infectious Disease Society of America
      Diagnosis and treatment of diabetic foot infections.
      These included an infection severity classification scale that was subsequently validated and shown to predict clinical outcomes.
      • Lavery L.A.
      • Armstrong D.G.
      • Murdoch D.P.
      • Peters E.J.
      • Lipsky B.A.
      Validation of the Infectious Diseases Society of America's diabetic foot infection classification system.
      These documents, taken together, represent the most comprehensive multinational attempt to codify a treatment approach to a condition that contributes to 71,000 lower extremity amputations per year in the United States alone (www.diabetes.org). Although an updated set of DFI Guidelines is slated to be published by the IDSA Committee sometime in 2010, and several new studies specifically investigating antibiotic treatment of DFIs have been published in the past 6 years,
      • Rao N.
      • Lipsky B.A.
      Optimising antimicrobial therapy in diabetic foot infections.
      many of the original points presented in the Executive Summary of the original document are still valid and deserving of review. Furthermore, the validated severity classification scale is now widely accepted and used to classify patients enrolled in DFI studies and will remain unchanged in the updated document.

      Severity scale

      Many classification systems have been developed to categorize diabetic foot wounds (especially ulcerations), some of which include the presence or absence of infection. None of these, however, have specifically classified the severity of infection. Probably the most recognized, and most venerable, system was that proposed by Wagner.
      • Van Acker K.
      • De Block C.
      • Abrams P.
      • et al.
      The choice of diabetic foot ulcer classification in relation to the final outcome.
      In this classification with four grades, more useful as a descriptor of size and depth of a wound, the presence of an infection is not considered until a Grade III ulceration, which is described as a deep ulcer with abscess, osteomyelitis, or joint sepsis. It is reasonable to ask, why can't a less extensive Grade 0, I, or II ulcer become infected? A newer, validated system first proposed by investigators at the University of Texas diabetic foot group is a derivation of the Wagner scheme.
      • Armstrong D.G.
      • Lavery L.A.
      • Harkless L.B.
      Validation of a diabetic wound classification system The contribution of depth, infection, and ischemia to risk of amputation.
      This system includes infection as a comorbidity modifier that can be added to any wound depth category, but it does not specify the severity of the infection.
      In order to address the lack of an adequate severity score for DFI, the IWGDF and the IDSA have each developed a mostly interchangeable, four level grading system specifically for infection (Table I). The presence of infection in a foot wound is defined clinically, not by a positive culture. Ulcerations are classified as either uninfected (lacking clinical evidence of purulence or inflammation) or infected, with a severity of mild, moderate, or severe. The differentiation between these categories is based on clinical signs and symptoms, thus corroborating the importance of making a clinical diagnosis of infection, as spelled out in point #5 of the Executive Summary described below. This scale has been validated in a prospective observational study published by Lavery et al.
      • Lavery L.A.
      • Armstrong D.G.
      • Murdoch D.P.
      • Peters E.J.
      • Lipsky B.A.
      Validation of the Infectious Diseases Society of America's diabetic foot infection classification system.
      When applied to 1666 patients with a foot ulceration, there was a significant increase in rates of hospitalization and lower extremity amputation with increased severity of the infection. These classification systems have now been widely accepted and are being employed in academic and clinical circles. Some clinicians have taken to combining systems that rate the size/depth of a wound, with infection severity (eg, “the patient presents with a University of Texas 2B wound with an IDSA category moderate infection”). One of the benefits of the infection severity scheme is that it can be used to help select an appropriate antibiotic regimen for DFIs, as shown in Table II.
      Table IClinical classification schemes (Infectious Diseases Society of America [IDSA] and International Working Group on the Diabetic Foot [IWGDF]) for a diabetic foot infection
      The presence of critical ischemia of the affected limb often increases the severity of the infection.
      Clinical manifestations of infectionIDSA infection severityIWGDF PEDIS grade
      International Consensus on the Diabetic Foot PEDIS system: perfusion, extent/size, depth/tissue loss, infection, and sensation.
      Wound lacking purulence or any manifestations of inflammationUninfected1
      Presence of purulence or ≥2 manifestations of inflammation (pain, tenderness, erythema, warmth, or induration), but any cellulitis/erythema extends ≤2 cm around the ulcer, and infection is limited to the skin or superficial subcutaneous tissues; no other local complications or systemic illness.Mild2
      Infection (as defined above) in a patient who is systemically well and metabolically stable, but which is associated ≥1 of the following characteristics: cellulitis extending >2 cm, lymphangitic streaking, spread beneath the superficial fascia, deep-tissue abscess, gangrene, and involvement of muscle, tendon, joint, or bone.Moderate3
      Infection in a patient with signs or symptoms of systemic toxicity (eg, fever, chills, leukocytosis) or metabolic instability (eg, tachycardia, hypotension, confusion, vomiting, acidosis, severe hyperglycemia, or azotemia)Severe4
      a The presence of critical ischemia of the affected limb often increases the severity of the infection.
      b International Consensus on the Diabetic Foot PEDIS system: perfusion, extent/size, depth/tissue loss, infection, and sensation.
      Table IISuggested antibiotic regimens for diabetic foot infections, based on clinical severity
      Reprinted from Lipsky et al.
      • Lipsky B.A.
      • Berendt A.R.
      • Deery H.G.
      • Embil J.
      • Joseph W.S.
      • Karchmer A.W.
      • et al.
      Infectious Disease Society of America
      Diagnosis and treatment of diabetic foot infections.
      Agent(s)MildModerateSevere
      Advised routeOral for mostOral or parenteral, based on clinical situation and agent(s) selectedIntravenous, at least initially
      Dicloxacillin
      Clindamycin
      Cephalexin
      Trimethoprim-sulfamethoxazole
      Amoxicillin/clavulanate
      Levofloxacin
      Cefoxitin
      Ceftriaxone
      Ampicillin/sulbactam
      Linezolid
      Where methicillin-resistant Staphylococcus aureus infection is proven or likely.
      ± aztreonam
      Ertapenem
      Cefuroxime ± metronidazole
      Ticarcillin/clavulanate
      Piperacillin/tazobactam
      Levofloxacin or ciprofloxain + clindamycin
      Imipenem-cilastatin
      Vancomycin
      Where methicillin-resistant Staphylococcus aureus infection is proven or likely.
      + ceftazidime ± metronidazole
      Similar agents of the same class may be substituted. Some of these regimens may not have FDA approval for complicated skin and skin structure infections, and only linezolid is currently specifically approved for diabetic foot infections.
      a Where methicillin-resistant Staphylococcus aureus infection is proven or likely.

      Executive summary review

      The IDSA DFI guidelines contained a 19-point Executive Summary with the key recommendations for diagnosing and treating these infections. The recommendations still remain valid and are critical to a successful approach to managing DFIs. We will address a few of the most important recommendations numbering them as they were in the 2004 guidelines, to make for easier reference to the original document. The original text is in bold italicized print, followed by our commentary.
      • 2
        Diabetic foot infections require attention to local (foot) and systemic (metabolic) issues and coordinated management, preferably by a multidisciplinary footcare team. The team managing these infections should include, or have ready access to, an infectious diseases specialist or a medical microbiologist. Apropos this special issue jointly published by the American Podiatric Medical Association and the Society for Vascular Surgery, the concept of a multidisciplinary team approach cannot be overstated. The team requires members trained in the skill set necessary for limb salvage and includes those concentrating on not only the anatomic disturbances of the lower extremity but also the perfusion to the limb. This approach (ie, care for the diabetic foot wound by at least an irreducible team of a foot specialist and a vascular surgeon) is aptly named the “toe and flow” concept (Armstrong, DA personal communication), an issue recognized in #14 below.
      • 4
        Aerobic gram-positive cocci (especially Staphylococcus aureus) are the predominant pathogens in diabetic foot infections. Patients who have chronic wounds, or who have recently received antibiotic therapy, may also be infected with gram-negative rods, and those with foot ischemia or gangrene may have obligate anaerobic pathogens. It has become increasingly clear that Staphylococcus aureus, including methicillin-resistant strains (MRSA), and Streptococcus spp, most often Group B, are the primary pathogens in most DFI. A number of studies have shown that antibiotic therapy directed at just these organisms can be successful, even when culture results demonstrate various other gram-negative bacteria or obligate anaerobes. This has led to the promulgation of the “Head of the Snake” concept—the aerobic gram-positive bacteria constitute the crucial head of the snake, while other isolated organisms are part of the body. If antibiotic therapy is directed at the primary organisms, thereby “cutting off the head” of the snake, the residual “body” would die. Thus, antibiotic therapy can often be narrowly targeted at only aerobic gram-positive cocci.
      • 5
        Wound infections must be diagnosed clinically on the basis of local (and occasionally systemic) signs and symptoms of inflammation. Laboratory (including microbiological) investigations are of limited use for diagnosing infection, except in cases of osteomyelitis. This point represents a cultural shift away from oft-practiced technology- (mostly imaging) based approach to diagnosis. In order to diagnose infection in a diabetic foot wound, the patient should present with at least two of the clinical signs and symptoms of inflammation including; erythema, edema, warmth, tenderness, induration, or pain. Cultures should be obtained, not to diagnose the infection, but rather to determine which organism is causing the clinically diagnosed infection in order to aid in antibiotic selection. A recent IWGDF consensus statement on diabetic foot osteomyelitis suggests that culture-based diagnosis and treatment are likely the best predictors of a positive outcome.
        • Berendt A.R.
        • Peters E.J.
        • Bakker K.
        • Embil J.M.
        • Eneroth M.
        • Hinchliffe R.J.
        • et al.
        Diabetic foot osteomyelitis: a progress report on diagnosis and a systematic review of treatment.
        Even in cases of osteomyelitis, the role of diagnostic imaging studies has been recently challenged. Currently, magnetic resonance imaging is the best imaging study for defining both soft tissue and bone infections.
        • Teh J.
        • Berendt T.
        • Lipsky B.A.
        Rational imaging Investigating suspected bone infection in the diabetic foot.
        Other studies have been investigated, however, with positron emission tomography (FDG-PET) combined with computed tomography scanning being the most promising.
        • Nawaz A.
        • Torigian D.A.
        • Siegelman E.S.
        • Basu S.
        • Chryssikos T.
        • Alavi A.
        Diagnostic performance of FDG-PET, MRI, and plain film radiography (PFR) for the diagnosis of osteomyelitis in the diabetic foot.
      • 9
        Available evidence does not support treating clinically uninfected ulcers with antibiotic therapy. Antibiotic therapy is necessary for virtually all infected wounds, but it is often insufficient without appropriate wound care. Inappropriate use of antibiotics leads to bacterial resistance. This observation has gained greater importance with the development of resistance of the common gram-positive pathogens, especially MRSA.
        • Bowling F.L.
        • Jude E.B.
        • Boulton A.J.
        MRSA and diabetic foot wounds: contaminating or infecting organisms?.
        • Dang C.N.
        • Prasad Y.D.
        • Boulton A.J.
        • Jude E.B.
        Methicillin-resistant Staphylococcus aureus in the diabetic foot clinic: a worsening problem.
        An increasing threat of treating soft tissue infections, including DFI, is the varying levels of tolerance of formerly susceptible microorganisms to vancomycin.
        • Gould I.M.
        Clinical relevance of increasing glycopeptide MICs against Staphylococcus aureus.
        This can take the form of just increasing minimum inhibitory concentrations (“MIC creep”) or frank resistance (vancomycin-resistant S. aureus, or VRSA). In fact, the first two reported cases of VRSA
        Centers for Disease Control and Prevention (CDC)
        Vancomycin-resistant Staphylococcus aureus–Pennsylvania, 2002.
        back in 2002 were isolated from diabetic foot wounds. With advances in the agents available for antibiotic treatment of these resistant gram-positive organisms has come a newer threat (eg, multi-drug resistant (MDR) gram-negative bacteria). Organisms, such as species of Klebsiella and Proteus, once relatively susceptible to a wide range of antibiotics, now may produce extended-spectrum beta-lactamases (ESBL) or carbapenemases, rendering them resistant to most commonly used drugs.
        • Varaiya A.
        • Dogra J.
        • Kulkarni M.
        • Bhalekar P.
        Extended spectrum beta lactamase (ESBL) producing Escherichia coli and klebsiella pneumoniae in diabetic foot infection.
        A major reason for the emergence of these resistant organisms is inappropriate, typically unnecessary, and overlong, antibiotic treatment.
      • 10
        Select an empirical antibiotic regimen on the basis of the severity of the infection and the likely etiologic agent(s). Therapy aimed solely at aerobic gram-positive cocci may be sufficient for mild-to-moderate infections in patients who have not recently received antibiotic therapy. Broad-spectrum empirical therapy is not routinely required but is indicated for severe infections, pending culture results and antibiotic susceptibility data. Take into consideration any recent antibiotic therapy and local antibiotic susceptibility data, especially the prevalence of methicillin-resistant S. aureus (MRSA) or other resistant organisms. Definitive therapy should be based on both the culture results and susceptibility data and the clinical response to the empirical regimen. The previously discussed “head of the snake” paradigm addresses initiating antibiotic therapy aimed principally (if not solely) at aerobic gram-positive organisms for many DFI. Even the 2004 Guidelines acknowledged the increasing prevalence of MRSA, but the problem has clearly worsened in most parts of the world. At the time the Guidelines were prepared, clinical trials specifically looking at antimicrobial management of DFI were sparse, and rates of MRSA isolation were 10% or less. More recent work has shown that these rates are increasing.
        • Lipsky B.A.
        • Tabak Y.P.
        • Johannes R.S.
        • Vo L.
        • Hyde L.
        • Weigelt J.A.
        Skin and soft tissue infections in hospitalised patients with diabetes: culture isolates and risk factors associated with mortality, length of stay and cost.
        In some institutions, MRSA has supplanted methicillin-susceptible S. aureus (MSSA) as the primary pathogen isolated in DFI. This raises the important question: When should empiric MRSA coverage be instituted? As stated in the summary point, the decision to cover MRSA should be based on knowledge of local prevalence, but at what “breakpoint” is the decision made? Unfortunately, there are no hard (or easy) and fast rules. The severity of the infection along with the risk tolerance of the clinician should each probably play a role. For mild infections, clinicians may tolerate a higher local prevalence or risk of MRSA infection before initiating empiric MRSA therapy, since the patient may do well with local wound care regardless of whether or not the organism is covered. However, for moderate to severe infections, the threshold for initiating anti-MRSA therapy should be lower (eg, an expected prevalence of >10%) given the potential for serious sequelae if aggressive antibiotic therapy is not initiated. This has given rise to the concept of “escalation” or “de-escalation” therapies for empiric MRSA coverage. If the organism is not empirically covered, the clinician can always “escalate” (broaden the spectrum) the choice of therapeutic agents to include MRSA once initial culture results are received. Likewise, if there is a greater concern that it may be present, broader spectrum empiric coverage is begun with the option of “de-escalation” (narrowing the spectrum) if cultures reveal only susceptible organisms. The availability of several new anti-MRSA antibiotic agents has made covering this organism easier than it was a decade ago.
        • Nicolau D.P.
        • Stein G.E.
        Therapeutic options for diabetic foot infections: a review with an emphasis on tissue penetration characteristics.
      • 14
        Seek surgical consultation and, when needed, intervention for infections accompanied by a deep abscess, extensive bone or joint involvement, crepitus, substantial necrosis or gangrene, or necrotizing fasciitis. Evaluating the limb's arterial supply and revascularizing when indicated are particularly important. Surgeons with experience and interest in the field should be recruited by the foot-care team, if possible. This final point is at the heart of the entire “toe and flow” concept. By the definition used by the US Food and Drug Administration, a complicated skin and skin structure infection (cSSSI) is one in which the patient either has a significant underlying medical comorbidity or an immunocompromising disease; in these cases, the potential for greater severity of the infection may require more aggressive surgical approaches (eg, incision and drainage or resection of infected and necrotic tissue). Although appropriate antibiotic therapy can be critical in achieving optimal outcomes, for many moderate to severe DFI, surgical intervention can be key to limb salvage. A recent consensus statement from the IWGDF
        • Berendt A.R.
        • Peters E.J.
        • Bakker K.
        • Embil J.M.
        • Eneroth M.
        • Hinchliffe R.J.
        • et al.
        Diabetic foot osteomyelitis: a progress report on diagnosis and a systematic review of treatment.
        classified DFI surgery as being “urgent” only in cases of necrotizing or deep soft tissue infections, major abscess, or gangrene. “Nonurgent” surgery may be needed when there is risk of significant compromise of the soft tissue envelope, loss of mechanical function, or if the degree of bone involvement is life- or limb-threatening. However, none of this “toe” surgery can be accomplished without adequate “flow” to the limb. Likewise, antibiotic therapy of the “toe” infection needs adequate “flow” to achieve therapeutic levels (of antibiotic and leukocytes) in the target infected tissues.
      Thus, a full circle is completed from the first executive summary review point to the last. A team approach is required, with specialists who are interested in foot infections and who possess the necessary skill set to succeed at diabetic limb salvage. Optimal outcomes for patients presenting with DFIs have repeatedly been shown to depend on care by a team of specialists, including those with training in podiatric and vascular surgery along with infectious diseases, diabetes, wound care, and internal medicine. To this end, the IDSA DFI Committee has been expanded to include stakeholders from specialties across the spectrum of diabetic foot care, including podiatric surgery and vascular surgery. All of these voices will be included in the 2010 update.

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