Clinical Setting

Empiric therapy.
- Empiric drug regimens should cover both staph and strep; role of enterococci is uncertain.
- Severe limb and/or life-threatening infections require initial parenteral therapy with predictable activity against Gram-positive cocci, coliforms and other aerobic Gram-negative rods and anaerobic Gram-negative bacilli.
- Risk of osteomyelitis increased if ulcer area >2 cm², positive probe to bone, ESR >70 and abnormal plain x-ray.

Diagnosis

MRI is best imaging modality: negative MRI reduces likelihood of osteomyelitis (JAMA 299:806, 2008).
Review of diagnostic accuracy of probe to bone (Clin Infect Dis 2016;63:944 and Clin Infect Dis 2016;63:949)

Etiologies

Ulcer, but no inflammation
- Colonizing skin flora
Ulcer with superficial inflammation
- Staphylococcus aureus
- Streptococcus agalactiae (Group B)
- Streptococcus pyogenes
Ulcer with inflammation, extension into fascia
- As above + coliforms (+ pseudomonas in patients with recent antibotic exposure, immunocompromise, prior isolation of pseudomonas in culture)
Extensive local inflammation and deep tissue invasion plus systemic toxicity
- As above + anaerobes

Primary Regimens

Optimal local wound care, including pressure off-loading, and peripheral vascular evaluation if indicated.
Ulcer, but no inflammation: No antimicrobial therapy recommended.
- Moderate strength evidence for improved healing with biologic skin equivalent or negative pressure wound therapy: Ann Intern Med 159:532, 2013.
Ulcer with superficial inflammation, no complicating features:
- Oral therapy, empirical regimen to cover MRSA: TMP-SMX DS 1-2 tabs po bid or Doxycycline 100 mg po bid or (Linezolid 600 mg po bid + Levofloxacin 750 mg po once daily)
- Oral therapy, mild infection, no purulence or low risk for MRSA: Cephalexin 500 mg qid or Cefpodoxime 200 mg po q12h or Levofloxacin 750 mg po q24h or Amoxicillin-clavulanate 875/125 po bid
  - TMP-SMX DS 1-2 tabs po bid or Doxycycline 100 mg po bid are also options.
Ulcer with inflammation, extension into deeper tissues:
- Oral therapy: (Amoxicillin-clavulanate 875/125 po bid + TMP-SMX DS 1-2 tabs po bid) or [(Levofloxacin 750 mg po q24h or Moxifloxacin 400 mg po q24h) + Linezolid 600 mg po bid] OR
- Parenteral therapy: (Ampicillin-sulbactam 3 gm IV q6h or Ertapenem 1 gm IV q24h) + Vancomycin 15-20 mg/kg IV q8-12h to achieve preferred target AUC₂₄ 400-600 μg/mL x hr (see vancomycin AUC dosing calculator; alternative is trough of 15-20 μg/mL) until MRSA is excluded.
Extensive local inflammation plus systemic toxicity, possibility of pseudomonal infection based on risk factors:
- Vancomycin 15-20 mg/kg IV q8-12h to achieve preferred target AUC₂₄ 400-600 μg/mL x hr (see vancomycin AUC dosing calculator; alternative is trough of 15-20 μg/mL) + Piperacillin-tazobactam 4.5 gm IV (over 4 hr) q8h
- Vancomycin as above + (Imipenem-cilastatin 0.5 gm IV q6h or Meropenem 1 gm IV q8h)
Diabetic foot osteomyelitis (see Medicina. 2021; 57:339)
- Surgical management
  - Surgical incision, drainage, and debridement indicated for presence of extensive bony destruction, nonviable/necrotic tissue
  - Limb ischemia and spreading soft tissue infection are associated with worse prognosis and may require partial or total amputation to remove infected and necrotic tissue
- Medical therapy
  - Should be pathogen-directed, based on results of culture and susceptibility testing
  - Limited data suggest that outcomes with 3 weeks of therapy following surgical debridement are comparable to the more traditional 6-week duration (Clin Infect Dis. 2021; 73:e1539-e1545).
  - 1 to 3 weeks of therapy may be sufficient if surgical margins are clean and free of residual osteomyelitis either histopathologically or microbiologically
  - Oral therapy is an option provided that agents with good oral bioavailability can be used.

Alternative Regimens

Extensive local inflammation plus systemic toxicity:

Daptomycin 6 mg/kg IV q24h or Linezolid 600 mg po bid are alternatives for Vancomycin
(Levofloxacin 750 mg IV q24h or Aztreonam 2 gm IV q8h) + Metronidazole 0.5 gm IV q6-8h are alternatives for Ampicillin-sulbactam or Piperacillin-tazobactam
Amoxicillin-clavulanate 1000/200 mg IV q8h (where available)

Duration of Therapy

7-10 days depending on clinical response, severity of infection and presence of complications if no osteomyelitis.
See above for medical and surgical management of osteomyelitis.

Antimicrobial Stewardship

Improved outcomes of more effective and faster wound healing of diabetic foot ulcer with negative-pressure wound therapy.
Obtain cultures of inflamed ulcer or wound to permit targeted antimicrobial therapy: de-escalate/modify regimen based on culture and susceptibility data.
Oral therapy with a bioavailable antibiotic as effective as parenteral therapy.

Comments

For review see Curr Opin Infect Dis 2016; 29:145-52.
See IDSA practice guidelines for additional treatment options: Clin Infect Dis. 2023 Oct 2:ciad527.
For primary and secondary preventive measures see: N Engl J Med 2017; 376: 2367
Amoxicillin-clavulanate 875/125 mg bid is an effective oral option for diabetic foot infection with or without osteomyelitis (Diabetes Obes Metab. 2019;21:1483–1486)
TMP-SMX may cause hyperkalemia in diabetics.
Use the higher dose of TMP-SMX in those with BMI > 40.

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