Skin Infections in Diabetes Mellitus

Aka: Skin Infections in Diabetes Mellitus, Diabetic Foot Infection, Cellulitis in Diabetes Mellitus, Cellulitis in Diabetic Foot, Infected Diabetic Foot Ulcer, Infection of Foot Associated with Diabetes

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II. Epidemiology

  1. Lower Extremity Amputations related to Diabetic Foot Infections in 130,000 patients/year (2016, U.S.)
    1. Amputations are associated with a 50% five-year mortality
    2. Armstrong (2020) J Foot Ankle Res 13(1): 16 [PubMed]

III. Risk Factors: Diabetic Foot Infections

  1. Peripheral Arterial Disease
  2. Peripheral Neuropathy
    1. Foot Ulcers are asymptomatic in 50% of patients with Neuropathy
  3. Immunodeficiency
  4. Foot deformities (e.g. Bunions, Charcot Foot)

IV. Pathophysiology

  1. Most common organisms are still aerobic Gram Positive Cocci
    1. Staphylococcus aureus is most common cause
    2. Methicillin-Resistant Staphylococcus aureus (MRSA) is present in 10-32% of diabetic infections
    3. Other common Gram Positive Bacteria
      1. Staphylococcus epidermidis
      2. Streptococcus agalactiae
      3. Enterococcus
  2. Risk factors for polymicrobial infections (50-80%) and especially Gram Negative infections (30-40%)
    1. More common in Chronic Wounds or recent antibiotics
    2. Requires broader spectrum antibiotic use
      1. Enterobacteriaceae
      2. Pseudomonas aeruginosa
  3. Risk factors for anaerobic infections (one third of wound cultures)
    1. Necrotic wounds
    2. Ischemic foot infections
    3. Organisms to cover
      1. Bacteroides fragilis
      2. Prevotella
      3. Porphyromonas
      4. Clostridium

V. Examination

  1. Evaluate severity of infection
    1. Distribution of infection
    2. Depth of infection
      1. See Probe-to-Bone Test (evaluation for Osteomyelitis)
    3. Associated systemic signs and symptoms
  2. Neurovascular examination
    1. Evaluate for Diabetic Neuropathy
    2. Evaluate for limb ischemia (Peripheral Arterial Disease)
      1. Evaluate distal pulses
      2. Evaluate for pale or cold distal extremeties
      3. Consider Ankle-Brachial Index or arterial duplex Ultrasound
  3. Diabetic control
    1. Metabolic abnormalities

VI. Differential Diagnosis

  1. Local Trauma
  2. Gouty Arthritis
  3. Acute Charcot Neuroarthropathy
  4. Fracture
  5. Deep Venous Thrombosis
  6. Limb Ischemia
  7. Venous Stasis

VII. Diagnosis: Local Infection

  1. Requires 2 classic findings of inflammation or purulence
    1. Local Swelling or induration
    2. Local tenderness or pain
    3. Local increased warmth
    4. Erythema >0.5 cm around an ulcer in any direction (may be non-contiguous)
    5. Purulent drainage
  2. Other findings suggestive of infection
    1. Local wound refractory to standard therapy
    2. Non-purulent persistent drainage
    3. Malodor or friable tissue

VIII. Grading: Diabetic Wound Severity (IWGDF Grade or IDSA classification)

  1. Grade 1: Not infected
    1. See local infection diagnostic criteria above
    2. Consider other causes of inflammatory response (see differential diagnosis as above)
  2. Grade 2: Mild infection
    1. Local infection of skin or subcutaneous tissue (no deep tissue involvement) or
    2. Erythema around wound site measuring 0.5 to 2 cm
  3. Grade 3: Moderate infection
    1. Erythema around wound site measuring >2 cm and/or
    2. Local infection extending deeper than subcutaneous tissue (tendon, Muscle, joint or bone involvement)
      1. May include subcutaneous abscess, Osteomyelitis, Septic Arthritis or Necrotizing Fasciitis
    3. Grade 3-4 are associated with increased amputation rates
  4. Grade 4: Severe infection
    1. Local infection AND
    2. Systemic Inflammatory Response Syndrome (SIRS)
  5. Modifiers
    1. Add "(O)" to grade 3 or 4 for infection involving bone (Osteomyelitis)
  6. References
    1. Lipsky (2012) Diabetes Metab Res Rev 28(suppl 1): 163-78 [PubMed]

IX. Labs

  1. Complete Blood Count
    1. Leukocytosis is absent in 50% of cases of Diabetic Foot Infection
    2. Neutrophil Count is normal in over 80% of Diabetic Foot Infections
  2. C-Reactive Protein (preferred) or Erythrocyte Sedimentation Rate
    1. Erythrocyte Sedimentation Rate >70 mm/hour correlates with Diabetic Foot Infection
  3. Wound culture
    1. Avoid superficial culture swabs due to inaccuracy from contamination
    2. Currettage from debrided ulcer base or obtain deep specimen tissue biopsy or Incision and Drainage
  4. MRSA Nasal swab
    1. Negative swab significantly decreases the chance of MRSA Wound Infection
      1. Acquisto (2018) Emerg Med J 35(6): 357-60 [PubMed]
  5. Procalcitonin
    1. Consider in unclear cases

X. Imaging: Suspected Osteomyelitis

  1. See Diabetic Foot Osteomyelitis
  2. XRay extremity
    1. See Osteomyelitis XRay
    2. Baseline study observing for local bone destruction, gas formation or foreign body
    3. Poor Test Sensitivity (as low as 25%), especially in early diabetic ulcers or mild infections (under a few weeks in duration)
  3. MRI (preferred)
    1. See Osteomyelitis MRI
    2. Characterizes deep infection involvement
    3. Detects Osteomyelitis (Test Sensitivity 90%)
  4. CT
    1. See Osteomyelitis CT
    2. Alternative when MRI contraindicated or unavailable
  5. Bone Scan
    1. See Osteomyelitis Bone Scan
    2. Replaced by MRI or CT in most cases
    3. Triple Phase Bone Scan Test Sensitivity for Osteomyelitis 90%, but Specificity is only 46%
    4. White Blood Cell scans increase sensitivity

XI. Management: Cellulitis in Comorbid Diabetes Mellitus

  1. Antibiotic Course
    1. IV antibiotics for first 5-7 days for severe infections and Osteomyelitis
    2. Duration 7-14 days
      1. Extend to 21-28 days for slowly resolving infections
      2. Extend to 4-6 weeks for Osteomyelitis
  2. Antibiotic Coverage
    1. Streptococcus
    2. Staphylococcus aureus
      1. Assume MRSA (unless negative nasal swab)
    3. Enterobacteriaceae and Anaerobic Bacteria
      1. Moderate to severe infections
      2. Recurrent infections
      3. Infections with severe limb ischemia
    4. Pseudomonas
      1. Moist environments
      2. Indwelling devices
      3. Other risk factors (age >65 years, Tobacco Abuse, Peripheral Arterial Disease, severe infection)
        1. Farhat (2017) Open Forum Infect Dis 4(Suppl 1): S108 [PubMed]
  3. Early or Mild disease (1 agent protocol)
    1. Indications
      1. Mild infections without Skin Ulcer or other Traumatic entry and no systemic findings
      2. For concerns regarding MRSA, use 2 agent protocol as below
        1. Consider MRSA nasal swab (negative swab may be used to narrow antibiotic spectrum)
    2. May start with typical Cellulitis management
      1. Cephalexin (Keflex) 500 mg orally every 6 hours or
      2. Dicloxacillin 500 mg orally every 6 hours
    3. Indications for Amoxicillin/Clavulanate or Augmentin (gram-negative and Anaerobe coverage)
      1. Antibiotics within the last month (Gram Negative infection)
      2. Necrosis or foul odor (anaerobic infection)
    4. Indications for Pseudomonas coverage in mild infections
      1. Water exposure (e.g. hot tub, lake, swimming pool)
      2. Indwelling devices
  4. Early or Mild disease (2 agent protocol)
    1. Course: 1-2 weeks
    2. Agent 1: MRSA Coverage (choose one)
      1. Trimethoprim-Sulfamethoxazole (Septra, Bactrim) DS one to two tabs orally twice daily (preferred)
      2. Alternative agents in Sulfa Allergy
        1. Minocycline 100 mg orally twice daily or
        2. Doxycycline 100 mg orally twice daily or
        3. Clindamycin (risk of induced resistance)
    3. Agent 2: Streptococcus coverage (choose one)
      1. Dicloxacillin 500 mg orally four times daily or
      2. Cephalexin 500 mg orally four times daily or
      3. Penicillin VK 500 mg orally four times daily
  5. Moderate disease
    1. Agent 1: MRSA Coverage (choose one)
      1. Vancomycin 30 mg/kg IV every 12 hours (first-line for MRSA)
      2. See oral MRSA agents above (mild disease) and IV MRSA agents below (severe disease)
    2. Agent 2: Streptococcus coverage (choose one)
      1. Gram Positive Coverage only
        1. Nafcillin 1 to 2 g IV every 4 hours or
        2. Cefazolin 1 to 2 g IV every 8 hours
      2. Gram Positive, Gram Negative and Anerobe Coverage
        1. Ampicillin/Sulbactam (Unasyn) 3 g IV every 6 hours or
        2. Ceftriaxone 1-2 g IV every 24 hours AND Metronidazole IV/PO every 8 hours or
        3. Ertapenem (Invanz) 1 gram IV every 24 hours
      3. Gram Positive, Gram Negative, Anaerobe and Pseudomonas (see Fluoroquinolone for risks)
        1. Levofloxacin 750 mg IV/PO every 24 hours (increasing resistance) or
        2. Delafloxacin 300 mg IV every 12 hours (or 450 mg orally every 12 hours)
  6. Severe disease (e.g. fever, systemic symptoms or signs)
    1. Course: 2-3 weeks with initial inpatient Parenteral antibiotics
    2. Agent 1: MRSA coverage (choose one)
      1. Vancomycin 30 mg/kg IV every 12 hours (first-line for MRSA) or
      2. Daptomycin 4 mg/kg IV q24 hours or
      3. Linezolid 600 mg IV or PO every 12 hours or
      4. Tigecycline (Tygacil) 100 mg IV load and then 50 mg IV every 12 hours
    3. Agent 2: Streptococcus and Enterobacteriaceae, Pseudomonas and Anaerobes (choose one)
      1. Carbapenem (preferred)
        1. Imipenem/Cilastin (Primaxin) 500 mg IV every 6 hours (preferred) or
        2. Ertapenem (Invanz) 1 gram IV q24 hours or
        3. Doripenem 500 mg IV q8 hours or
        4. Meropenem 1 gram IV q8 hours
      2. Alternative agents
        1. Piperacillin-Tazobactam (Zosyn) 4.5 g IV every 6 hours or
        2. Cefepime 2 g IV every 8 hours AND Metronidazole 500 mg IV every 8 hours

XII. Management: Diabetic Foot Ulcer and Infection

  1. See Diabetic Foot Ulcer
  2. See Suspected Osteomyelitis in Diabetes Mellitus
  3. Wound care
    1. Clense and debride wounds
    2. Probe-to-Bone Test
  4. Antibiotic Course: 7-14 days for mild infections
    1. Longer course (3-4 weeks) may be needed in more severe, slowly resolving infections
  5. Isolated Skin Ulcer without inflammation
    1. No antibiotics required
    2. See Diabetic Foot Ulcer for wound management
  6. Ulcer with superficial inflammation (2 agent protocol to cover for Streptococcus and Staphylococcus aureus)
    1. Agent 1: MRSA Coverage (choose one)
      1. Trimethoprim-Sulfamethoxazole (Septra, Bactrim) DS one to two tabs orally twice daily (preferred) or
      2. Doxycyline 100 mg orally twice daily
    2. Agent 2: Streptococcus coverage (choose one)
      1. Augmentin XR 2000/125 orally twice daily (esp. if Anaerobes suspected - necrosis, odor) or
      2. Cephalexin 500 mg orally every 6 hours or
      3. Cefprozil 500 mg orally every 12 hours or
      4. Cefpodoxime 200 mg every 12 hours or
      5. Cefuroxime 500 mg orally every 12 hours or
      6. Levofloxacin 750 mg orally daily
  7. Ulcer with >2 cm inflammation and fascia extension
    1. Additionally cover for Gram Negative Bacteria (risk of Osteomyelitis)
    2. Oral Protocol 1
      1. Trimethoprim-Sulfamethoxazole (Septra, Bactrim) DS one to two tabs orally twice daily AND
      2. Amoxicillin-Clavulanate (Augmentin) XR 2000/125 orally twice daily
    3. Oral Protocol 2
      1. Linezolid 600 mg orally twice daily AND
      2. Fluoroquinolone (Ciprofloxacin 750 mg twice daily or Levofloxacin 750 mg daily)
    4. Parenteral Protocol (2 agents)
      1. Agent 1: MRSA Coverage (choose 1)
        1. Vancomycin 30 mg/kg IV every 12 hours (first-line for MRSA) or
        2. Linezolid 600 mg orally twice daily or
        3. Daptomycin 6 mg/kg IV q24 hours
      2. Agent 2: Based on local susceptibilities (choose 1)
        1. Unasyn 3 g IV every 6 hours or
        2. Imipenem 0.5 g IV every 6 hours or
        3. Ertapenem 1 g IV every 24 hours or
  8. Ulcer with extensive inflammation, deep space invasion and systemic toxicity (cover for Anaerobes, Pseudomonas)
    1. Agent 1: MRSA Coverage (choose 1)
      1. Vancomycin 30 mg/kg IV every 12 hours (first-line for MRSA) or
      2. Linezolid 600 mg orally twice daily or
      3. Daptomycin 6 mg/kg IV q24 hours
    2. Agent 2: Streptococcus, Anaerobe, Pseudomonas coverage
      1. Zosyn 3.375 g IV every 6 hours or
      2. Imipenem/Cilastin (Primaxin) 500 mg IV every 6 hours or
      3. Meropenem 1 g IV every 8 hours or
      4. Metronidazole 500 mg orally every 6-8 hours AND (Ciprofloxacin or Levofloxacin or Aztreonam)
  9. Other adjunctive antibiotic options
    1. Rifampin
      1. Consider as adjunctive in Diabetic Foot Osteomyelitis
      2. Wilson (2019) JAMA Netw Open 2(11):e1916003 +PMID:31755948 [PubMed]

XIII. Management: Intensive Management Indications

  1. Hospitalization Indications
    1. Moderate infection hospitalization indications
      1. Comorbid Peripheral Arterial Disease
      2. Poor glycemic control
      3. Unreliable patient for maintaining antibiotic regimen, wound care, off-loading and close follow-up
    2. Severe infection or systemic infection with signs of toxicity
    3. Metabolic instability
    4. Rapidly progressive or deep infection
    5. Significant wound necrosis
    6. Gangrene
    7. Limb-critical ischemia
    8. Urgent or emergent intervention required
  2. Surgery Indications (tissue and bone culture, Wound Debridement, revascularization, amputation)
    1. Deep abscess
    2. Bone or joint extensively involved
    3. Crepitation
    4. Significant wound necrosis
    5. Gangrene
    6. Necrotizing Fasciitis

XIV. Complications: Diabetic Foot Osteomyelitis

  1. See Diabetic Foot Osteomyelitis
  2. Epidemiology
    1. Present in 20% of mild to moderate Diabetic Foot Infections
    2. Present in up to 60% of severe Diabetic Foot Infections
  3. Indications to evaluate for Osteomyelitis
    1. Foot Ulcers >2 cm in diameter
    2. Foot Ulcers >3mm deep
    3. Foot Ulcers overlying a bony prominence
    4. Chronic Diabetic Foot Ulcers refractory to healing
    5. Probe-to-Bone Test positive (or bone visible)

XV. Prevention

  1. See Diabetic Foot Care
  2. See Diabetic Foot Ulcer
  3. Avoid foot injuries (avoid barefoot walking)
  4. Identify Diabetic Neuropathy and emphasize daily home foot inspection for new lesions
  5. Daily foot care and examination to catch Foot Wounds early (cuts, Blisters)
  6. Foot exam at each clinic visit (socks and shoes off!)
    1. Assess for Diabetic Neuropathy with monofilament test (at least once yearly)
  7. Careful wound care
  8. Unload extremity of local pressure sources
    1. Examples: non-weight bearing, well-fitting shoes, Orthotics
    2. Keeping pressure off wound is far more important than any particular Wound Dressing choice
  9. Optimize glycemic control
  10. Tobacco Cessation

XVI. References

  1. (2021) Presc Lett 28(9): 53
  2. (2019) Sanford Guide, accessed on IOS 2/12/2020
  3. Hellekson (2005) Am Fam Physician 71:1429-33 [PubMed]
  4. Gemechu (2013) Am Fam Physician 88(3):177-84 [PubMed]
  5. Lipsky (2012) Clin Infect Dis 54(12): e132-73 [PubMed]
  6. Matheson (2021) Am Fam Physician 104(4): 386-94 [PubMed]

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