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Jun.26.2021

Diabetic Foot Infection

Synopsis

Key Points

  • Diabetic foot infection is an infection, often originating from an ulcer, that occurs in a patient with diabetes mellitus
    • Clinically important because it heals slowly, can progress, and is associated with high morbidity and serious complications (eg, osteomyelitis, gangrene, amputation)
  • Clinical presentation varies widely, depending on extent and duration of infection and patient's degree of sensory impairment
    • Local features include purulence, erythema, induration, tenderness, or calor
    • May be accompanied by systemic indicators of infection such as fever or hypothermia, tachycardia, or tachypnea
  • Diagnosis is clinical, based on the presence of local and systemic signs and symptoms of inflammation
    • Plain radiographs are indicated in all patients; perform MRI if abscess or osteomyelitis is suspected
    • Obtain a CBC, serum chemistries, and sedimentation rate or C-reactive protein level in all patients whose clinical examination suggests infection; consider measuring procalcitonin
    • Obtain deep cultures after thorough cleansing and preliminary debridement
    • Assess vascular status in all patients, beginning with ankle-brachial index
  • Infection may be classified as follows according to the IDSA and IWGDF:
    • Uninfected (grade 1): no symptoms or signs of infection
    • Mild (grade 2): infection is confined to skin and subcutaneous tissue; erythema, if present, extends no further than 2 cm around the ulcer
    • Moderate (grade 3): infection extends beneath subcutaneous tissue, or erythema exceeds a 2-cm rim around the ulcer
    • Severe (grade 4): local infection is associated with 2 or more signs of systemic infection
  • Treatment includes antibiotic therapy and wound care
    • Antibiotic therapy is recommended for all patients; selection of empiric regimens is based on severity of infection and risk factors for MRSA and Pseudomonas aeruginosa
    • Aggressive wound care is essential, beginning with surgical debridement
    • Offloading of pressure is critical to healing, but it must allow frequent wound inspection and dressing changes until infection clears
  • Prognosis is guarded; about 20% of moderate to severe infections require amputation; in the remainder, healing is often very slow and/or incomplete
  • Prevention focuses on avoiding injury and ulceration through education, structural deformity correction, and vulnerable surface protection through use of orthotics and prescription shoes; good glycemic control and regular follow-up are also essential

Urgent Action

  • Severe diabetic foot infection carries significant risk of limb loss and may be life-threatening
    • These patients require urgent hospitalization, antibiotics, and surgical evaluation

Pitfalls

  • Patients at highest risk for infection lack the ability to perceive it because they often have sensory neuropathy and retinopathy; family members or other caretakers must be vigilant on patient's behalf for signs of foot injury and infection
  • Infection often leads to hyperglycemia and may precipitate diabetic ketoacidosis or other metabolic derangements
  • Differentiating between soft tissue infection, osteomyelitis, and Charcot osteoarthropathy may be difficult and require multimodal imaging r1

Terminology

Clinical Clarification

  • Diabetic foot infection is an infection, often originating from an ulcer, that occurs in a patient with diabetes mellitus
    • Clinically important because it heals slowly, can progress, and is associated with high morbidity and serious complications (eg, osteomyelitis, gangrene, amputation)
  • Spectrum of disease varies from superficial local cellulitis to chronic osteomyelitis
    • Osteomyelitis is present in about 20% of diabetic foot infections r2

Classification

  • Many diabetic foot ulcer classifications exist r3
  • IDSA (Infectious Diseases Society of America) and IWGDF (International Working Group on the Diabetic Foot) classification consists of four grades of severity for diabetic foot infection ranging from uninfected to severe infection; these correspond to the IWGDF PEDIS (perfusion, extent, depth, infection, and sensation) grades 1 through 4 r4
    • Scores for both scales are based on signs, symptoms, and extent of local infection, and on the presence or absence of signs of systemic infection
      • Used to determine which patients require hospital admission for intravenous antibiotics
    • Uninfected (grade 1): no symptoms or signs of infection
      • No purulence or inflammation
    • Mild (grade 2): infection is confined to skin and subcutaneous tissue
      • 2 or more of the following manifestations of inflammation:
        • Purulence
        • Erythema
        • Tenderness
        • Warmth
        • Induration
      • Any cellulitis/erythema extends 2 cm or less around the ulcer
      • No other local complications or systemic illness
    • Moderate (grade 3): infection extends beneath subcutaneous tissue
      • 1 or more of the following:
        • Cellulitis extending more than 2 cm
        • Lymphangitic streaking
        • Spread beneath the superficial fascia
        • Deep-tissue abscess
        • Gangrene
        • Involvement of muscle, tendon, joint, or bone
      • Patient is systemically well and metabolically stable
    • Severe (grade 4): local infection with signs of systemic involvement
      • Patient has signs of systemic toxicity or metabolic instability: r5
        • Fever or chills (temperature more than 38 °C or less than 36 °C)
        • Tachycardia (more than 90 beats per minute)
        • Hypotension
        • Confusion
        • Vomiting
        • Leukocytosis (WBC count greater than 12,000/mm³, or less than 4000/mm³, or more than 10% immature [band] forms)
        • Acidosis
        • Severe hyperglycemia
        • Azotemia
        • Tachypnea (more than 20 breaths per minute)
  • Another classification schema is the Wound, Ischemia, and Foot Infection system r4
    • Assesses 1-year risk for amputation and 1-year benefit for revascularization based on combination of scores for the following:
      • Wound (based on depth of ulcer or extent of gangrene)
      • Ischemia (based on ankle pressure, toe pressure, or TcPO₂ [transcutaneous oxygen pressure])
      • Foot infection (based on IWGDF/IDSA criteria)

Diagnosis

Clinical Presentation

History

  • Clinical presentation varies, depending on extent and duration of infection and patient's degree of sensory impairment
  • Pain may be a presenting symptom in patients who can perceive it
    • Patients with advanced diabetic neuropathy may not experience pain, even in the presence of a severe infection; those with impaired vision (eg, severe retinopathy) may not be able to see signs of infection to report them
  • Fever or chills may occur, as may other systemic symptoms such as nausea or vomiting
  • Because blood glucose becomes more difficult to control in the presence of infection, some symptoms may relate to hyperglycemia, including the following:
    • Blurred vision
    • Polyuria
  • In addition to presenting complaints, other important patient history information includes the following:
    • Previous foot ulcers and outcomes
    • Amputations
    • Vascular surgery or angioplasty
    • Vascular symptoms (eg, claudication, rest pain)
    • Symptoms of neuropathy (eg, paresthesias, numbness)
    • Other indicators of advanced diabetes (eg, renal insufficiency, diabetic retinopathy)
    • Smoking habits (past and present)

Physical examination

  • Assess patient's general appearance; those with severe infection may be pale or flushed, restless, or confused
  • Vital signs may be abnormal; fever is common. Patients with severe infection may be febrile or hypothermic, tachycardic, tachypneic, and/or hypotensive
  • Foot examination
    • Assess for infection, defined by the presence of 2 or more of the following:
      • Purulence
      • Erythema
      • Induration
      • Tenderness
      • Increased temperature in overlying or surrounding skin
    • Additional assessment includes:
      • Appearance of wound and exposed tissue
        • Paleness may indicate significant ischemia; blood- or beefy-red tissue may indicate better perfusion
        • Presence of eschar or necrotic material
        • Visible or palpable bone at base
          • Gently insert a blunt metal probe to determine whether the base of the wound is soft tissue or bone
          • Exposed bone is associated with osteomyelitis
        • Size of the ulcer
      • Fluctuance or crepitus on palpation
      • Sensation (eg, pinprick or monofilament, vibratory, proprioceptive)
      • Structural changes contributing to ulceration and infection (eg, Charcot arthropathy, bunion, hammer toe)
      • Edema, which may impede perfusion
      • Skin changes associated with chronic ischemia (eg, shiny appearance, lack of hair)
      • Pulses (ie, dorsalis pedis, posterior tibial)
        • May be diminished; a handheld Doppler may aid in identifying the flow

Causes and Risk Factors

Causes

  • Most commonly caused by infection of a preexisting diabetic foot ulcer
    • Foot ulcers are common in patients with diabetes and result from a complex interplay of neuropathy and ischemia that causes structural changes and results in weight-bearing shifts, callus formation, and friction
  • Other breaks in skin integrity, including traumatic wounds and tinea pedis, also may serve as sources of infection
  • Impaired immune function and hyperglycemia foster infection in ulcers and other wounds and skin lesions predisposed to infection
  • Most infections are polymicrobial r5r6
    • Staphylococci (including MRSA) and streptococci are most common
    • Aerobic gram-negative bacilli (eg, Escherichia coli) are frequently involved, especially in patients who have received previous antibiotics
    • Anaerobes may play a role in ischemic or necrotic tissue

Risk factors and/or associations

Other risk factors/associations
  • Limb ischemia due to peripheral artery disease increases the risk of a diabetic foot ulcer becoming infected r5
  • The following wound characteristics are associated with a higher risk for infection: r7
    • Neuropathic or traumatic wound
    • Exposed bone
    • Prolonged (more than 30 days) or recurrent wound
  • Risk factors for foot ulcers, a common precursor to diabetic foot infection, include the following: r8r9
    • Foot deformity
    • Peripheral neuropathy with loss of protective sensation
    • Peripheral vascular disease
    • Poor glycemic control
    • Diabetic nephropathy
    • Visual impairment
    • Previous foot ulcer
    • Previous amputation
    • Cigarette smoking
    • Calluses or corns
    • Chronic kidney disease

Diagnostic Procedures

Primary diagnostic tools

  • Clinical diagnosis is based on the presence of local signs and symptoms of inflammation, with or without systemic signs
  • Evaluation begins with a thorough history and physical examination
  • Assess wound characteristics, if present
    • Define extent (size) and depth of wound after cleaning and debridement
      • Probe-to-bone test for open wounds r5
        • Gently insert a blunt sterile metal probe through the wound to determine if the wound is through to the bone (detected by hard, gritty feel)
        • This test can help diagnose (when likelihood is high) or exclude (when likelihood is low) osteomyelitis
  • Obtain specimens of infected wounds for culture after cleaning and debridement r5r6
    • Do not culture clinically uninfected wounds
    • Collect a tissue specimen from wound by curettage or biopsy r5
    • In patients with suspected osteomyelitis, arrange for bone biopsy to obtain culture and histopathology
  • Obtain CBC, serum chemistries, and sedimentation rate or C-reactive protein in all patients whose clinical examination suggests infection; consider measuring procalcitonin level r6r10
    • Inflammatory markers can be a useful adjunctive measure for establishing the diagnosis when examination is equivocal r5
  • Assess severity of infection using classification scheme from the IDSA/IWGDF r4
    • Based on extent and depth of infection and presence of systemic signs of infection
    • Can guide choice of empiric antibiotic regimen, route of administration, and help determine need for hospitalization
  • Obtain ankle-brachial index or toe-brachial index to assess vascular supply, particularly in patients with nonpalpable or weak distal pulses r5r11
    • Further evaluation of vascular supply (eg, angiography) may be indicated in some patients, but usually not acutely
  • Imaging is indicated if suspect infective complications such as deep abscess or osteomyelitis, or alternative diagnosis of Charcot arthropathy r1
    • Plain radiographs are recommended for all patients as the initial study, but the radiographs may be negative early in the infection course r5r12
    • MRI is the most sensitive study for detecting osteomyelitis, especially early in the infection course, and can detect soft tissue abscess r5
    • If MRI cannot be done, CT, bone scan, or a radionuclide-labeled WBC scan with/without SPECT (single-photon emission computed tomography) or SPECT/CT is recommended when osteomyelitis is suspected r6r13

Laboratory

  • CBC
    • Elevated WBC count supports the diagnosis of infection, but a normal value does not exclude it
      • Criteria for severe infection include the following: r5r6
        • WBC levels below 4000 cells/mm³
        • WBC levels above 12,000 cells/mm³
        • Left shift with 10% or more immature cells
  • Serum chemistry studies
    • Infection may be associated with hyperglycemia; correction of hyperglycemia is associated with lower complication rates in hospitalized patients r14
    • Renal insufficiency may limit antibiotic choices or necessitate dose adjustments
  • Erythrocyte sedimentation rate
    • Elevated rate is associated with infection; can use serial measurements to assess response to treatment
    • Level higher than 60 mm/hour suggests underlying osteomyelitis, especially in conjunction with an ulcer depth of 3 mm or more and a C-reactive protein of 3.2 mg/dL or higher r15
  • C-reactive protein
    • Elevated level is associated with infection; can use serial measurements to assess response to treatment
    • Level higher than 3.2 mg/dL suggests associated osteomyelitis, especially in conjunction with an ulcer depth of 3 mm or more and a sedimentation rate of 60 mm/hour or higher r15
  • Procalcitonin
    • Elevated procalcitonin, especially in conjunction with an elevated C-reactive protein, can help discriminate infection from other conditions (eg, noninfected ulcer) r5r16
  • Cultures
    • Deep cultures of soft tissue, obtained by biopsy or curettage after debridement and lavage, may identify most accurately the infecting organism(s) r5

Imaging r1r13

  • Plain radiograph of foot
    • Useful in further defining bony deformities (Charcot foot) and may show osteomyelitis (periosteal elevation, cortical erosion) or even a foreign body
    • Presence of radiolucent gas bubbles in soft tissue can indicate severe infection (eg, gas gangrene, necrotizing fasciitis) r2
    • In patients whose imaging studies are negative initially, serial radiographs during course of treatment are recommended to enable early detection of developing osteomyelitis r12
  • MRI of foot
    • Most sensitive and specific imaging test for diagnosing osteomyelitis and defining extent of disease r17
    • Normal marrow signal essentially excludes diagnosis of osteomyelitis
  • CT of foot r13r17
    • Can be used to assess bone and joint involvement adjacent to diabetic foot ulcers
    • Shows characteristic changes associated with osteomyelitis more clearly than plain radiographs but less sensitive for infection than MRI r13r17
  • Radionuclide-labeled WBC scan
    • May be done in conjunction with 3-phase bone scan and/or SPECT or SPECT/CT of foot r13
    • Indicated when osteomyelitis is suspected and MRI cannot be performed; also helpful in discriminating infection from other abnormalities associated with orthopedic hardware, previous surgery, or trauma
    • In the presence of neuropathic arthropathy, scans may be positive or indeterminant, but a negative scan excludes the diagnosis of osteomyelitis

Procedures

Bone biopsy r6r18
General explanation
  • Sampling of bone for histopathologic examination and microbiologic culture
  • Specimens may be obtained via surgical or percutaneous bone biopsy or they may be obtained during debridement
    • In stable patients, in whom there is minimal soft tissue infection, ideally obtain specimens before initiating antibiotics
    • In patients with significant soft tissue infection, do not delay antimicrobial therapy
    • Ideally percutaneous biopsy should be performed through intact skin to reduce culture contamination; however, often performed through the ulcer in practice r18
  • Perform both aerobic and anaerobic cultures on biopsy specimens
Indication
  • Use in patients with suspected osteomyelitis associated with diabetic foot infection to make a definitive diagnosis and identify causative pathogen
Interpretation of results
  • Gold standard for diagnosis of osteomyelitis is positive culture result from bone biopsy accompanied by histopathologic signs of necrosis
  • Histopathologic analysis shows necrotic bone and inflammatory exudate
  • Culture results identify causative pathogens and show antimicrobial susceptibility pattern

Other diagnostic tools

  • Ankle systolic pressure and ankle-brachial index r11
    • Recommended for all patients with diabetic foot infection or ulcer, especially if pulses are diminished or absent
    • Accuracy in predicting peripheral artery disease is variable, especially in the presence of neuropathy or arterial calcification, but the test is noninvasive, easy to do, and requires no special equipment r19
      • Place blood pressure cuff above ankle and measure ankle systolic blood pressure (dorsalis pedis and/or posterior tibial artery) with the aid of a handheld Doppler, if necessary r9
        • Also evaluate pedal Doppler arterial waveforms, which should be triphasic r11
      • Divide result by brachial systolic value to calculate the ankle-brachial index r9
        • Reference range is 0.90 to 1.3: peripheral arterial disease is unlikely r11
        • 0.6 to 0.89 indicates mild perfusion deficit and may be associated with claudication
        • 0.4 to 0.59 indicates moderate obstruction to perfusion
        • Less than 0.4 indicates severely reduced flow and may be associated with rest pain
        • More than 1.3 indicates arterial calcification and is an unreliable indicator of perfusion
  • Toe systolic pressure and toe-brachial index r11
    • Requires toe pressure cuff and handheld Doppler
    • Wrap toe cuff around great toe and measure systolic pressure using Doppler placed distal and medial to the cuff
    • Pressure lower than 30 mm Hg indicates significantly impaired perfusion
    • Divide result by brachial systolic value to calculate the toe-brachial index r11
      • Peripheral arterial disease is unlikely with toe-brachial index of 0.75 or greater
  • Skin perfusion pressure and transcutaneous oxygen pressure
    • Require special equipment, but help assess prognosis
    • Skin perfusion pressure less than 40 mm Hg or a TcPO₂ less than 25 mm Hg increases the likelihood of poor healing and amputation r11

Differential Diagnosis

Most common

  • Acute Charcot arthropathy
    • Deforming arthropathy (foot or ankle collapse) resulting from neuropathy, repetitive minor trauma, and bone remodeling
    • Like diabetic foot infection, may present as unilateral swelling of the foot with erythema and calor
    • Symptoms, signs, and laboratory evidence of infection are absent
    • Imaging (eg, MRI scan) may be necessary to definitively differentiate from diabetic foot infection, especially if there is a break in skin integrity that might have served as a portal for infection
  • Gout d1
    • Crystalline arthropathy caused by deposition of monosodium urate crystals
    • May present as a hot swollen joint (eg, first metatarsophalangeal joint, ankle) and may be associated with tenosynovitis; extremely painful in patients who have normal sensation
    • May be clinically indistinguishable from diabetic foot infection, although the latter usually has an identifying portal for infection
    • Elevated serum uric acid suggests the diagnosis, which can be confirmed by aspirating synovial fluid and demonstrating negatively birefringent crystals
  • Fracture
    • Fracture after unrecognized trauma may occur in patients with diabetes who have severe sensory impairment in their feet
    • Patient may present with swollen, erythematous foot, with or without pain or detectable tenderness
    • Differentiated by imaging; plain radiographs may or may not show fracture early on, and MRI may be necessary

Treatment

Goals

  • Eradicate infection, heal underlying wound if present, and prevent complications such as osteomyelitis or amputation

Disposition

Admission criteria

Admission is based on a combination of severity according to IDSA/IWDGF criteria and individual patient circumstances

  • Admit patients with severe diabetic foot infection or moderate diabetic foot infection that is complex or associated with significant comorbidities or lack of outpatient support r5
Criteria for ICU admission
  • Patients with severe infection (eg, gangrene, necrotizing infection) and hemodynamic instability or associated severe metabolic derangements (eg, diabetic ketoacidosis)

Recommendations for specialist referral

  • Specialist teams, where available, are recommended r10r20
  • Consult an infectious disease specialist to select empiric antibiotics, interpret culture results, and refine care regimen
  • Consult a surgeon with debridement expertise to debride open wounds; this may be a general or orthopedic surgeon or a podiatric surgeon with advanced training
  • Consult a vascular surgeon if there is evidence of ischemia to evaluate and determine whether revascularization is needed to improve management of infection and increase chance of healing
  • Consult a plastic or reconstructive surgeon if tissue replacement or wound coverage is required
  • Consult an endocrinologist to optimize control of blood glucose levels
  • Consult an orthopedist or a podiatrist for proper protective and offloading device to avoid pressure or friction on the affected area

Treatment Options

Cleanse and debride wounds or ulcers r5

  • Debridement is usually done surgically, but in some cases mechanical (eg, wet-to-dry dressings), autolytic, or combination debridement is appropriate r21
    • Serial debridement may be necessary
  • Drain deep collections; decompress compartments under pressure

Treat all patients with empiric antibiotics r5

  • No single regimen has proven superior; selection of antibiotics is determined by severity of infection and likely infecting pathogens and their antibiotic susceptibilities, risk of adverse effects and interactions r5
  • Parenteral antibiotics are indicated for initial treatment in patients with a severe diabetic foot infection; switch to oral therapy if patient shows clinical improvement and there is an appropriate oral agent available r5
  • Oral antibiotics are appropriate for most mild and some moderate infections at presentation
  • For mild to moderate infections in patients who have not recently received antibiotics (for this or other infections), use a regimen aimed at staphylococci and aerobic streptococci
    • For patients who have received antibiotics recently, use additional coverage for gram-negative bacilli
  • For severe infections, use broad spectrum therapy against both aerobic and anaerobic organisms
  • Empiric coverage of MRSA is recommended in the following circumstances:
    • Patients who have been infected or colonized with MRSA within the past year
    • Areas where local rate of methicillin resistance among Staphylococcus aureus isolates exceeds 30% (for moderate infection) to 50% (for mild infection)
    • Severe infections, in which delayed coverage while awaiting cultures is thought to pose an unacceptable risk to the patient
  • Consider coverage of Pseudomonas aeruginosa in patients with severe infection, macerated wounds, and in circumstances that foster its role as a pathogen (eg, warm, moist climate; frequent use of foot soaks) r5
  • The following agents may be used for empiric treatment of diabetic foot infections: r5r6
    • For mild infection in which MRSA is unlikely to play a role
      • Dicloxacillin or other penicillinase-resistant penicillin
      • Cephalexin or other first-generation cephalosporin
      • Clindamycin (if ß-lactam allergy or intolerance)
      • Levofloxacin (if recent antibiotic exposure)
      • Amoxicillin-clavulanate (if recent antibiotic exposure)
    • For mild infection with risk factors for MRSA
      • Doxycycline
      • Trimethoprim-sulfamethoxazole
      • Linezolid
      • Macrolide
    • For moderate or severe infections without risk factors for MRSA or Pseudomonas aeruginosa
      • Ampicillin-sulbactam
      • Amoxicillin-clavulanate
      • Cefoxitin or other second-generation cephalosporin
      • Ceftriaxone or other third-generation cephalosporin
      • Ertapenem (if recent antibiotic exposure or ischemia/necrosis or gas formation)
      • Piperacillin/tazobactam (if recent antibiotic exposure)
      • Second-/third-generation cephalosporin plus clindamycin or metronidazole (if ischemia/necrosis or gas formation)
      • Imipenem-cilastatin (if ischemia/necrosis or gas formation)
    • For moderate to severe infections with risk for Pseudomonas aeruginosa
      • Piperacillin-tazobactam
      • Imipenem-cilastatin
      • Penicillinase-resistant penicillin plus ceftazidime or ciprofloxacin
    • For moderate or severe infections with MRSA risk, add or substitute 1 of the following:
      • Linezolid
      • Daptomycin
      • Vancomycin or other glycopeptides
      • Doxycycline
  • National Institute for Health and Care Excellence provides antibiotic recommendations appropriate for the United Kingdom r20
  • When culture results are available, modify antibiotic regimen accordingly, if indicated
  • 1 to 2 weeks of antibiotics are sufficient for most soft tissue infections; continued treatment for up to 3 to 4 weeks is recommended if the infection is extensive, resolving slower than expected, or if patient has severe underlying peripheral artery disease r5
  • For osteomyelitis, regimens are similar to those for moderate to severe infection and usual treatment course is at least 4 weeks (but usually no longer than 6 weeks) r5r6d2
    • If the infected bone has been completely resected, aim therapy at treating any residual soft tissue infection; antibiotic therapy can be given for just a few days if there is no soft tissue infection
    • For patients with residual necrotic bone (ie, not adequately debrided), may continue antibiotics for 3 months or longer

Adjunctive therapy

  • Meticulous wound care is an essential part of treatment and involves the following:
    • Dressings to protect the wound and maintain a moist environment
    • Offloading of pressure from the wound, particularly when the plantar surface is involved r21
  • Early revascularization may be required to restore adequate blood supply for treatment of infection (delivery of antibiotics and host defenses) r5r10r11
  • Optimize glycemic control r10d3
    • Hyperglycemia in hospitalized patients is defined as blood glucose levels more than 140 mg/dL r22
    • Once insulin therapy is started, a target glucose range of 140 to 180 mg/dL is recommended for most critically ill patients and noncritically ill patients r22
  • The following measures are not routinely recommended: r5
    • Granulocyte colony stimulating factor r5r20r21
    • Topical antiseptics, silver preparations, honey, bacteriophage therapy
    • Negative pressure wound therapy
    • Hyperbaric oxygen therapy or topical oxygen therapy

Drug therapy

  • Penicillins
    • Dicloxacillin
      • Dicloxacillin Sodium Oral capsule; Children and Adolescents: 25 to 50 mg/kg/day PO divided every 6 hours (Max: 2 g/day) for 5 to 7 days.
      • Dicloxacillin Sodium Oral capsule; Adults: 500 mg PO 4 times daily for 5 to 7 days.
    • Amoxicillin-clavulanate
      • Amoxicillin Trihydrate, Clavulanate Potassium Oral tablet; Adults, Adolescents, and Children weighing 40 kg or more (every 8 hour regimens): 250 mg amoxicillin with 125 mg clavulanic acid PO every 8 hours (using 250 mg tablet) for mild/moderate infections and 500 mg amoxicillin with 125 mg clavulanic acid PO every 8 hours (using 500 mg regular tablets; 125 mg or 250 mg chewable tablets; or 125 mg/5 mL or 250 mg/5 mL suspension) for severe infections.
    • Ampicillin-sulbactam
      • Ampicillin Sodium, Sulbactam Sodium Solution for injection; Adults: 1.5 g (1 g ampicillin and 0.5 g sulbactam) or 3 g (2 g ampicillin and 1 g sulbactam) IV/IM every 6 hours. Duration depends on severity; typically 1 to 4 weeks.
    • Piperacillin-tazobactam
      • Piperacillin Sodium, Tazobactam Sodium Solution for injection; Adults: 3.375 g (3 g piperacillin and 0.375 g tazobactam) IV every 6 hours or 4.5 g (4 g piperacillin and 0.5 g tazobactam) IV every 8 hours.
  • Cephalosporins
    • Cephalexin
      • Cephalexin Monohydrate Oral capsule; Adults: 1 to 4 g daily, divided in 2 to 4 equal doses and generally 250 mg PO every 6 hours or 500 mg PO every 12 hours; higher doses for severe infections. Max: 4 g/day. Generally treat 7 to 14 days. Guidelines recommend 500 mg PO every 6 hours for methicillin-susceptible Staphylococcal aureus (MSSA) or streptococcal infections and 250 mg PO every 6 hours for 7 days impetigo or ecthyma.
    • Cefoxitin
      • Cefoxitin Sodium Solution for injection; Adults: 1 g IV/IM every 6 to 8 hours for uncomplicated infections, and 1 g IV every 4 hours or 2 g IV every 6 to 8 hours for moderately-severe or severe infections. For infections requiring higher doses, 2 g IV every 4 hours or 3 g IV every 6 hours can be used. Max: 12 g/day.
    • Ceftriaxone
      • Ceftriaxone Sodium Solution for injection; Adults: 1 to 2 g IV/IM every 12 to 24 hours (Max: 4 g/day) depending on severity of illness and causative organism for 1 to 2 weeks for moderate or severe diabetic wound infections.
  • Carbapenems
    • Ertapenem
      • Ertapenem Solution for injection; Adults: 1 g IV/IM once daily for 7 to 14 days. For mixed necrotizing skin infections, surgical intervention is primary therapeutic intervention. Treat until further debridement not necessary, patient improved clinically, and fever absent for 48 to 72 hours. Depending on severity of illness and causative organism, treat for 1 to 2 weeks for moderate or severe diabetic wound infections. For cat or dog bite, preemptive therapy for 3 to 5 days is recommended for patients who are immunocompromised, asplenic, have advanced liver disease, have edema of bite area, have moderate to severe injuries, or have penetrating injuries to periosteum or joint capsule.
    • Imipenem-cilastatin
      • Imipenem, Cilastatin Sodium Solution for injection; Adults: 500 mg IV every 6 hours or 1 g IV every 8 hours for fully susceptible organisms and 1 g IV every 6 hours for organisms with intermediate susceptibility.
  • Fluoroquinolones
    • Levofloxacin
      • Levofloxacin Oral tablet; Adults: 500 mg PO every 24 hours for 7 to 10 days for uncomplicated infections; 750 mg PO every 24 hours for 7 to 14 days for complicated infections. Clinical guidelines suggest treating for 1 to 2 weeks for mild/moderate diabetic foot infections.
  • Sulfonamide
    • Trimethoprim-sulfamethoxazole
      • Sulfamethoxazole, Trimethoprim Oral tablet; Adults: 160 to 320 mg trimethoprim/800 to 1,600 mg sulfamethoxazole PO every 12 hours for 5 to 10 days.
  • Lincosamide
    • Clindamycin
      • Clindamycin Solution for injection; Adults: 600 mg IV/IM every 8 hours to 900 mg IV every 8 hours for 7 to 14 days; however, treatment up to 28 days may be needed.
  • Tetracycline
    • Doxycycline
      • Doxycycline Hyclate Oral capsule; Adults, Adolescents, and Children 8 years and older and weighing 45 kg or more: 100 mg PO every 12 hours for 5 to 10 days for CA-MRSA plus a beta-lactam if beta-hemolytic streptococci coverage is necessary.
  • Glycopeptide
    • Vancomycin
      • Vancomycin Hydrochloride Solution for injection; Adults: 25 to 30 mg/kg (actual body weight) IV loading dose for seriously-ill patients, then 15 to 20 mg/kg/dose (actual body weight) IV every 8 to 12 hours per guidelines. Adjust dose based on serum concentrations. FDA-approved dosage is 500 mg IV every 6 hours or 1 g IV every 12 hours. Treat for 7 to 14 days for complicated skin and skin structure infections due to MRSA.
  • Oxazolidinone
    • Linezolid
      • Linezolid Oral tablet; Adults: 600 mg PO every 12 hours for 10 to 14 days. NOTE: Not studied for decubital ulcers. IDSA recommends 600 mg PO every 12 hours for 7 to 14 days as option for MRSA.
  • Lipopeptide
    • Daptomycin
      • Daptomycin Solution for injection; Adults: 4 mg/kg/dose IV every 24 hours for 7 to 14 days.

Nondrug and supportive care

Wound care

  • Numerous studiesr23 have sought to identify the optimal dressing, although most studies have been done on patients with noninfected diabetic foot ulcers; in that setting, no superior dressing has been identified. The IDSA makes the following general recommendations:r6
    • For dry or necrotic wounds, apply frequently moistened saline gauze or hydrogel dressings; the latter aid in autolytic debridement
    • Occlusive or semiocclusive dressings retain moisture in dry wounds
    • Alginates, foams, and hydrocolloid reduce or absorb exudate; the latter also facilitates autolytic debridement
    • Topical antimicrobial dressings (eg, silver-based) are not recommended
  • Offloading (ie, preventing pressure on the affected area) allows progressive healing, but it must be balanced with need for frequent dressing changes and wound inspections r24
    • Nonremovable knee-high offloading devices are the first choice for offloading treatment of noninfected foot ulcers, neuropathic plantar forefoot or midfoot diabetic foot ulcers, and those with either mild infection or mild ischemia r24
    • Removable knee-high offloading devices are considered as second line options and are acceptable for patients with both mild infection and mild ischemia or with either moderate infection or moderate ischemia; may also be considered for both moderate infection and moderate ischemia or with either severe infection or severe ischemia depending on patient's functional status and activity level r24
  • Other treatments that have not shown clear benefit and that are not currently routinely recommended for diabetic foot infections include hyperbaric oxygen, negative pressure wound therapy, sucrose-octasulfate impregnated dressings, autologous combined leucocyte, platelet and fibrin patches, and topical placental derived products r5r20
    • These treatments have been shown to help heal diabetic foot ulcers and may be considered to help heal certain refractory ulcers once infection is resolved r25
Procedures
Debridement
General explanation
  • Removal of infected, devitalized, and necrotic tissue. Usually done surgically (ie, sharp debridement), but auxiliary methods include mechanical (eg, wet-to-dry dressings) or chemical (eg, dressings that promote autolysis)
Indication
  • Presence of infected or necrotic tissue
Interpretation of results
  • Debridement is adequate when wound bed is clean and remaining tissue is red and bleeds easily

Comorbidities

  • Patients with coexisting atherosclerosis may require revascularization to heal or to optimize level of amputation
  • Many patients with diabetes also have ischemic heart disease, which may increase risk for surgical procedures r10

Monitoring

  • Inspect infected wounds frequently, daily while in hospital
    • Document wound size, extent of surrounding erythema, amount and character of drainage or exudate, and quality of exposed tissue. Periodic photographs are helpful

Complications and Prognosis

Complications

  • Severe infection may result in sepsis and death d4
  • Contiguous spread to bone or joint may lead to osteomyelitis or septic arthritis r26
  • Infection that cannot be controlled may necessitate amputation
  • Extensive infection may result in significant tissue loss and gait disturbance, exacerbating risk for further ulceration and infection
  • Infection may precipitate uncontrolled hyperglycemia, including diabetic ketoacidosis d5

Prognosis

  • Both short- and long-term prognosis are guarded
    • About 20% of moderate to severe infections require amputation at some level r27
    • At 1-year follow-up in a large series of patients with infected diabetic foot ulcer, 46% of patients had experienced resolution of infection and complete wound healing r6r28
      • 17% had required amputation
      • 15% had died
    • Overall mortality 5 years after an amputation for diabetic foot infection is 70% r27
    • Osteomyelitis is associated with more surgeries and amputations, longer hospitalizations, and higher rates of recurrent infection and readmission for infection compared to moderate and severe diabetic foot infection involving soft tissue only r29
      • Over 80% of patients with diabetic foot osteomyelitis require amputation  r18
  • In an individual patient, favorable prognostic markers include the following: r11
    • Toe pressure 30 mm Hg or higher
    • Skin perfusion pressure 40 mm Hg or higher
    • Transcutaneous oxygen pressure 25 mm Hg or higher

Screening and Prevention

Prevention

  • Foot ulcers are a common precursor to infection, and all patients with diabetes should have their feet examined regularly to inspect for ulcers, calluses, skin changes, and deformities that predispose them to ulceration and to assess sensation and perfusion r9
    • American Diabetes Association recommends comprehensive foot examination at least annually; for patients who have a history of prior ulceration or amputation or who have evidence of sensory loss, inspect feet at every visit r8
    • Examine skin for color changes, dryness, cracking, maceration, and tinea pedis
    • Check for calluses, blisters, and ulcers
    • Note structural abnormalities (eg, Charcot arthropathy, bunions, hammer toes) that are subject to pressure and friction
    • Check sensation with a 10-g monofilament on plantar aspects of the hallux and on first, third, and fifth metatarsal heads. Also assess 1 or more of the following neurologic parameters, because reduced response may signal onset of neuropathy:
      • Vibration (128-Hz tuning fork) on plantar surface of the hallux
      • Pinprick sensation on the dorsal surface of the hallux just proximal to the nail
      • Temperature
    • Assess perfusion
      • Palpate pulses
      • In patients who have weak dorsalis pedis or posterior tibial pulses, obtain an ankle-brachial index
        • Place blood pressure cuff above the ankle and measure systolic blood pressure in the dorsalis pedis and/or posterior tibial artery, with the aid of a handheld Doppler, if necessary
        • Divide result by brachial systolic value to calculate ankle-brachial index r6r9
          • Reference range is 0.91 to 1.3
          • 0.6 to 0.89 indicates mild perfusion deficit and may be associated with claudication
          • 0.4 to 0.59 indicates moderate obstruction to perfusion
          • Less than 0.4 indicates severely reduced flow and may be associated with rest pain
          • More than 1.3 indicates arterial calcification and is an unreliable indicator of perfusion
    • Inspect shoes inside and out for areas of wear, rough interior surfaces, foreign bodies r3
      • Assess for proper fit while patient stands wearing shoe
        • Inside shoe length should be 1 to 2 cm longer than foot
        • Inside shoe width should accommodate widest point, usually across metatarsal heads
        • Height of toe box should accommodate without rubbing tops of all toes
      • Assess need for orthotic device or prescription shoe to accommodate deformities
  • Various risk classifications are used to guide recommendations for how to prevent foot ulcers including frequency of follow-up and protective measures r9
    • Risk stratification and guidance developed by American Diabetes Association is as follows:
      • Risk category 0: no loss of protective sensation, no peripheral vascular disease, and no deformity
        • Provide patient education and advice about appropriate footwear
        • Ideally, perform annual assessment
      • Risk category 1: loss of protective sensation with or without structural deformity
        • Consider prescriptive footwear
        • Consider surgical correction of deformity if footwear cannot be designed to accommodate it
        • Reinforce education
        • Reassess every 3 to 6 months
      • Risk category 2: peripheral artery disease with or without loss of protective sensation
        • Consider prescriptive footwear
        • Consider consulting and ongoing follow-up with a vascular specialist
        • Reassess every 2 to 3 months
      • Risk category 3: history of ulcer or amputation
        • Provide patient education and advice about appropriate footwear
        • If peripheral vascular disease is present, consider consultation and ongoing follow-up with a vascular specialist
        • Reassess every 1 to 2 months
    • Similar risk assessments and recommendations are also provided by the Society for Vascular Surgery/American Podiatric Medical Association/Society for Vascular Medicine,r12National Institute for Health and Care Excellence,r20 and IWGDF
  • Elements of patient education should include the following: r3
    • Daily foot inspection—including web spaces—by patient or caregiver
      • Notify health care provider immediately if there is a new wound of any kind, or if foot appears red or feels unusually warm
    • Foot care/hygiene
      • Wash feet daily, avoiding water that is higher than body temperature; dry carefully, including between toes
      • Lubricate dry skin with emollients, but avoid areas between toes
      • Do not attempt to remove calluses yourself; consult your health care provider
      • Cut toenails straight across; if unable (eg, inadequate vision, impaired mobility), get help from caregiver or professional
    • Appropriate footwear
      • Do not walk barefoot, or wear only socks or thin slippers without protective soles; wear shoes inside and outside home
      • Do not wear shoes that are too tight or have irregular inside surfaces that rub the skin
      • Inspect shoes and feel inside with hand to identify roughness or foreign objects before putting on shoe
      • Wear seamless socks and change daily to a clean pair; do not wear tight or knee socks
    • Do not use any kind of heating device to warm feet
    • Be sure that your health care provider examines your feet regularly
  • Tight glycemic control (for most patients, target hemoglobin A1C less than 7%) may delay development or slow progression of diabetic neuropathy and therefore of diabetic foot ulcers r22
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