What are the first-line antibiotic choices for treating cellulitis?

First-Line Antibiotics for Cellulitis

For uncomplicated cellulitis, a beta-lactam antibiotic such as cephalexin (500 mg orally four times daily) or dicloxacillin is recommended as first-line therapy for 5 days. 1

Treatment Algorithm Based on Severity and Risk Factors

Mild Non-Purulent Cellulitis (Outpatient)

• First-line: Beta-lactam antibiotics
  • Cephalexin 500 mg orally four times daily
  • Dicloxacillin 500 mg orally four times daily
  • Duration: 5 days (extend if not improved) 1

Moderate Non-Purulent Cellulitis or Risk Factors for MRSA

• Consider adding or switching to MRSA coverage if:

  • History of MRSA infection
  • Penetrating trauma
  • Injection drug use
  • MRSA colonization
  • Systemic inflammatory response syndrome (SIRS)
  • Treatment failure with beta-lactams 1

• MRSA-active options:

  • Trimethoprim-sulfamethoxazole (TMP-SMX)
  • Clindamycin 600 mg orally three times daily
  • Linezolid 600 mg orally twice daily 1, 2

Severe Non-Purulent Cellulitis (Inpatient)

• First-line: Vancomycin 15-20 mg/kg IV every 12 hours 1
• Alternative regimens:
  • Vancomycin plus piperacillin-tazobactam
  • Vancomycin plus imipenem/meropenem 1

Important Clinical Considerations

Microbiology

• Most cases of non-purulent cellulitis are caused by beta-hemolytic streptococci and methicillin-susceptible Staphylococcus aureus (MSSA) 2
• MRSA should be considered in specific risk populations or when first-line therapy fails 1, 2

Treatment Duration

• 5 days is typically sufficient for uncomplicated cellulitis
• Extend treatment if infection has not improved within 5 days 1

Adjunctive Measures

• Elevation of affected area to reduce edema and promote healing 1
• Examine interdigital toe spaces and treat any fissuring, scaling, or maceration to prevent recurrence 1
• Consider systemic corticosteroids (prednisone 40 mg daily for 7 days) in non-diabetic adults 1

Prevention of Recurrence

• Identify and treat predisposing conditions:
  • Edema
  • Obesity
  • Eczema
  • Venous insufficiency
  • Toe web abnormalities 1
• For patients with 3-4 episodes per year, consider prophylactic antibiotics:
  • Oral penicillin or erythromycin twice daily for 4-52 weeks
  • Intramuscular benzathine penicillin every 2-4 weeks 1

Common Pitfalls and Caveats

1. Overuse of broad-spectrum antibiotics: Beta-lactams remain effective first-line therapy for most cases of cellulitis. Adding MRSA coverage for all patients is unnecessary and may contribute to antibiotic resistance 1, 2

2. Inadequate treatment duration: While 5 days is sufficient for most cases, treatment should be extended if improvement is not seen 1

3. Failure to recognize treatment failure: Patients should show improvement within 48-72 hours. If not improving, consider:

   • Alternative diagnosis
   • Resistant organisms
   • Deeper infection
   • Need for surgical intervention 2

4. Neglecting supportive measures: Elevation of the affected area and treatment of predisposing factors are essential components of management 1

5. Misdiagnosis: Many conditions can mimic cellulitis. Consider alternative diagnoses if not responding to appropriate therapy 2

Recent clinical trials have shown that adding TMP-SMX to cephalexin did not significantly improve outcomes in uncomplicated cellulitis in the per-protocol analysis, though there was a trend toward benefit in the intention-to-treat analysis 3. This supports the IDSA guideline recommendation to use beta-lactams alone as first-line therapy for typical cases.