Skin Infections in Diabetes Mellitus

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

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II. Epidemiology

  1. Lifetime Incidence of Diabetic Foot Infections: 4%
  2. 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. Onset is typically with a unrecognized Diabetic Foot Wound
    1. Contributing factors include Diabetic Neuropathy, Immunosuppression of diabetes, Peripheral Arterial Disease
      1. Repeated unrecognized pressure or Trauma
      2. Delayed presentation despite advanced wounds
      3. Fungal infections (e.g. web spaces, Onychomycosis)
    2. Most Diabetic Foot Wounds are colonized with Bacteria chronically
      1. Acute infections present with purulence, erythema, edema, tenderness and induration
      2. Acute infections may rapidly spread through soft tissue compartments and involve underlying bone
      3. Acute inflammatory changes are variable, and may be decreased in peipheral arterial disease
    3. Most common infection entry sites
      1. Web spaces (60%)
      2. Nail source such as Onychomycosis, Paronychia (30%)
      3. Puncture Wounds (10%)
  2. Most common organisms are still aerobic Gram Positive Cocci (80% of organisms present on culture)
    1. Gram Positive Cocci are most common in previously untreated Diabetic Foot Infections
    2. Staphylococcus aureus is most common cause (27%)
      1. Up to 60% are Methicillin-Resistant Staphylococcus aureus (MRSA)
    3. Other common Gram Positive Bacteria
      1. Staphylococcus epidermidis
      2. Streptococcus agalactiae
      3. Enterococcus (13%)
  3. 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 (e.g. Escherichia coli, Proteus mirabilis)
      2. Pseudomonas aeruginosa (13%, esp. with soaked dressings)
  4. Risk factors for anaerobic infections (one third of wound cultures)
    1. Necrotic wounds
    2. Deep tissue wounds
    3. Ischemic foot infections
    4. Organisms to cover
      1. Bacteroides fragilis
      2. Prevotella
      3. Porphyromonas
      4. Clostridium

V. Exam: General

  1. See Cellulitis
  2. Vital Signs
  3. 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
  4. Diabetic control
    1. Metabolic abnormalities

VI. Exam: Infection

  1. Underlying wound
    1. See Diabetic Foot Ulcer
  2. Characteristics
    1. Purulent drainage
    2. Localized erythema, edema and induration
    3. Focal tenderness (may be absent in advanced Diabetic Neuropathy)
    4. May be associated with a foul odor, poor Wound Healing and friable tissue
  3. Distribution of infection
    1. Proximal spread (including ascending lymphangitis)
  4. Depth of infection
    1. See Probe-to-Bone Test (evaluation for Osteomyelitis)
    2. See Complications: Osteomyelitis as below
    3. Depth of infection and exposed tissue (deep Dermis, subcutaneous fat, Muscle, bone)
    4. Skin Abscess
  5. Associated systemic signs and symptoms (including SIRS criteria and Sepsis)
    1. Fever
    2. Tachycardia
    3. Tachypnea
  6. Severe infectious complications
    1. Necrotizing Fasciitis
      1. See Necrotizing Fasciitis
      2. Acute life-threatening, rapid infectious spread along fascial planes, typically by gas forming organisms
    2. Gangrene
      1. Ischemic, necrotic, shrunken red-black tissue
      2. Dry gangrene is seen with chronic limb ischemia (Peripheral Arterial Disease) without acute infection
      3. Wet gangrene occurs when ischemic tissue is acutely infected
        1. Medical emergency typically requiring amputation, and aggressive Resuscitation with broad Antibiotics
        2. Often associated with gas forming organisms

VII. Differential Diagnosis

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

VIII. 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

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

  1. See IDSA Diabetic Foot Wound Classification
  2. See University of Texas Diabetic Wound Classification
  3. See Wagner Ulcer Classification
  4. Grade 1: Not infected
    1. See local infection diagnostic criteria above
    2. Consider other causes of inflammatory response (see differential diagnosis as above)
  5. 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
  6. 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
  7. Grade 4: Severe infection
    1. Local infection AND
    2. Systemic Inflammatory Response Syndrome (SIRS)
  8. Modifiers
    1. Add "(O)" to grade 3 or 4 for infection involving bone (Osteomyelitis)
  9. References
    1. Lipsky (2012) Diabetes Metab Res Rev 28(suppl 1): 163-78 [PubMed]

X. 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 and/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

XI. 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

XII. 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 (6 to 8 weeks if not surgically debrided)
  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. Mild to Moderate disease without systemic findings (2 agent protocol)
    1. Indications
      1. More extensive wounds (e.g. deeper ulcers, >2 cm Cellulitis margins) without systemic findings
    2. Course: 1-2 weeks
    3. 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)
    4. Agent 2: Streptococcus coverage (choose one)
      1. See indications for alternative use of Augmentin or Pseudomonas coverage as above
      2. Dicloxacillin 500 mg orally four times daily or
      3. Cephalexin 500 mg orally four times daily or
      4. Penicillin VK 500 mg orally four times daily
  5. Moderate disease (systemic signs or symptoms)
    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 ParenteralAntibiotics
    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

XIII. 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. Unweight wounds (relieve pressure on wound site)
    3. 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]

XIV. 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. Necrotizing Fasciitis
    8. Limb Threatening Ischemia
    9. 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

XV. 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. Affects the forefoot in 90% of cases
  3. Most commonly affects the weight bearing bones ("foot tripod")
    1. First Metatarsal head
    2. Fifth Metatarsal head
    3. Calcaneous
  4. Indications to evaluate for Osteomyelitis
    1. Foot Ulcers >2 cm in diameter
    2. Foot Ulcers >3mm deep
    3. Erythrocyte Sedimentation Rate >70 mm3
    4. Chronic toe swelling
    5. Foot Ulcers overlying a bony prominence
    6. Chronic Diabetic Foot Ulcers refractory to healing
    7. Probe-to-Bone Test positive (or bone visible)

XVI. Prognosis

  1. Predictors that raise risk of failed treatment to 45% (compared with 10% when all are absent)
    1. Leukocytosis
    2. Increased C-Reactive Protein (C-RP)
    3. Increased Erythrocyte Sedimentation Rate (ESR)
    4. Severe wound grading (20% failure rates with 2B to 2D and 3B to 3D)
    5. Prior inpatient treatment
    6. Low Serum Albumin
  2. Other factors associated with treatment failure
    1. Methicillin Resistant Staphylococcus Aureus (MRSA) infection
    2. Fever
    3. Increased Serum Creatinine
    4. Gangrenous appearing foot lesions
  3. References
    1. Lipsky (2005) Lancet 366(9498):1695-703 [PubMed]
    2. Vardakas (2008) Diabetes Res Clin Pract 80(3):344-51 [PubMed]

XVII. 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

XVIII. References

  1. (2021) Presc Lett 28(9): 53
  2. (2019) Sanford Guide, accessed on IOS 2/12/2020
  3. Vadhan and Mehta (2024) Crit Dec Emerg Med 38(4): 26-31
  4. Hellekson (2005) Am Fam Physician 71:1429-33 [PubMed]
  5. Gemechu (2013) Am Fam Physician 88(3):177-84 [PubMed]
  6. Lipsky (2012) Clin Infect Dis 54(12): e132-73 [PubMed]
  7. Matheson (2021) Am Fam Physician 104(4): 386-94 [PubMed]
  8. Pitocco (2019) Eur Rev Med Pharmacol Sci 23(suppl 2):26-37 [PubMed]

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