What is the recommended treatment for cellulitis?

Treatment of Cellulitis

First-Line Antibiotic Therapy

Beta-lactam monotherapy is the standard of care for typical uncomplicated cellulitis, with a 96% success rate, and MRSA coverage is unnecessary in most cases. 1, 2

Recommended Oral Regimens for Uncomplicated Cellulitis

• Cephalexin 500 mg four times daily for 5 days 1
• Dicloxacillin 250-500 mg every 6 hours for 5 days 1, 2
• Amoxicillin (standard dosing) for 5 days 1, 2
• Penicillin V 250-500 mg four times daily for 5 days 1
• Clindamycin 300-450 mg every 6 hours for 5 days (covers both streptococci and MRSA, useful for penicillin allergy) 1, 2

Treatment Duration

Treat for exactly 5 days if clinical improvement occurs; extend only if symptoms have not improved within this timeframe. 1, 2 This represents a major shift from traditional 7-14 day courses and is supported by high-quality randomized controlled trial evidence. 1

When to Add MRSA Coverage

Do NOT routinely add MRSA coverage for typical nonpurulent cellulitis. 1, 2 MRSA is an uncommon cause of typical cellulitis even in high-prevalence settings. 1, 3

Specific Indications for MRSA Coverage

Add MRSA-active antibiotics ONLY when these risk factors are present: 1, 2

• Penetrating trauma or injection drug use 1
• Purulent drainage or exudate 1
• Known MRSA colonization or prior MRSA infection 1
• Systemic inflammatory response syndrome (SIRS) 1
• Failure to respond to beta-lactam therapy after 48 hours 1

MRSA-Active Regimens

When MRSA coverage is needed: 1

• Clindamycin monotherapy 300-450 mg every 6 hours (covers both streptococci and MRSA, but only if local resistance <10%) 1, 2
• Trimethoprim-sulfamethoxazole PLUS a beta-lactam (e.g., cephalexin) 1
• Doxycycline 100 mg twice daily PLUS a beta-lactam 1

Critical pitfall: Never use doxycycline or trimethoprim-sulfamethoxazole as monotherapy for cellulitis—their activity against beta-hemolytic streptococci is unreliable. 1, 2

Intravenous Therapy for Hospitalized Patients

Indications for Hospitalization

Admit patients with: 1, 2

• Systemic inflammatory response syndrome (SIRS), fever, hypotension, or altered mental status 1
• Severe immunocompromise or neutropenia 1
• Concern for necrotizing fasciitis or deeper infection 1
• Failure of outpatient therapy 2

IV Antibiotic Selection

For uncomplicated cellulitis requiring hospitalization (no MRSA risk factors): 1

• Cefazolin 1-2 g IV every 8 hours (preferred) 1
• Oxacillin 2 g IV every 6 hours (alternative) 1

For complicated cellulitis or MRSA coverage needed: 1, 2

• Vancomycin 15-20 mg/kg IV every 8-12 hours (first-line, A-I evidence) 1
• Linezolid 600 mg IV twice daily (equally effective alternative, A-I evidence) 1
• Daptomycin 4 mg/kg IV once daily (A-I evidence) 1

Severe Cellulitis with Systemic Toxicity

For signs of systemic toxicity, rapid progression, or suspected necrotizing fasciitis, use mandatory broad-spectrum combination therapy: 1, 2

• Vancomycin 15-20 mg/kg IV every 8-12 hours PLUS piperacillin-tazobactam 3.375-4.5 g IV every 6 hours 1
• Alternative: Linezolid PLUS piperacillin-tazobactam 1
• Alternative: Vancomycin PLUS a carbapenem (meropenem 1 g IV every 8 hours) 1

Duration for severe infections: 7-14 days guided by clinical response, not the standard 5 days. 1

Essential Adjunctive Measures

These are often neglected but critical for treatment success: 1, 2

• Elevate the affected extremity above heart level for at least 30 minutes three times daily to promote gravity drainage 1, 2
• Examine and treat interdigital toe spaces for tinea pedis, fissuring, scaling, or maceration 1, 2
• Address venous insufficiency and lymphedema with compression stockings once acute infection resolves 1, 2
• Consider systemic corticosteroids (prednisone 40 mg daily for 7 days) in non-diabetic adults, though evidence is limited 1

Special Situations

Bite-Associated Cellulitis

Amoxicillin-clavulanate (Augmentin) 875/125 mg twice daily as monotherapy for animal or human bite-associated cellulitis (provides polymicrobial coverage). 1

Penicillin Allergy

• Clindamycin 300-450 mg every 6 hours (covers both streptococci and MRSA) 1, 2
• Levofloxacin 500 mg daily for 5 days (reserve for beta-lactam allergies; does not cover MRSA reliably) 1

Cephalosporin Allergy

• Penicillin V 250-500 mg four times daily (safe in isolated cephalosporin allergy) 1
• Clindamycin 300-450 mg every 6 hours 1

Prevention of Recurrent Cellulitis

Annual recurrence rates are 8-20% in patients with previous leg cellulitis. 1

For patients with 3-4 episodes per year despite treating predisposing factors, consider prophylactic antibiotics: 1, 2

• Penicillin V 250 mg orally twice daily 1, 2
• Erythromycin 250 mg twice daily 1, 2
• Intramuscular benzathine penicillin 2

Critical Pitfalls to Avoid

• Do not add MRSA coverage reflexively simply because the patient is hospitalized—beta-lactam monotherapy succeeds in 96% of typical cases 1, 3, 4
• Do not extend treatment beyond 5 days unless symptoms have not improved 1, 2
• Do not use doxycycline or trimethoprim-sulfamethoxazole as monotherapy for typical cellulitis 1
• Do not delay surgical consultation if necrotizing fasciitis is suspected (severe pain out of proportion to exam, skin anesthesia, rapid progression, gas in tissue, bullous changes) 1
• Do not miss pseudocellulitis mimics such as venous stasis dermatitis, contact dermatitis, or lymphedema 4

Reassessment and Treatment Failure

Mandatory reassessment in 24-48 hours to verify clinical response. 1 If cellulitis is spreading despite appropriate antibiotics:

• Reassess for MRSA risk factors 1
• Evaluate for necrotizing fasciitis (emergent surgical consultation if suspected) 1
• Consider misdiagnosis (pseudocellulitis, DVT, other mimics) 4
• Switch to vancomycin or linezolid if MRSA suspected 1