What is the first-line treatment for cellulitis?

First-Line Treatment for Cellulitis

Beta-lactam monotherapy is the standard of care for typical uncomplicated cellulitis, with oral cephalexin 500 mg every 6 hours or dicloxacillin 250-500 mg every 6 hours for 5 days as the preferred first-line agents. 1

Primary Treatment Approach

Recommended oral beta-lactam options include: 1

• Cephalexin 500 mg four times daily
• Dicloxacillin 250-500 mg every 6 hours
• Penicillin
• Amoxicillin
• Amoxicillin-clavulanate

For hospitalized patients requiring IV therapy: 1

• Cefazolin 1-2 g IV every 8 hours is the preferred agent
• Nafcillin is an alternative for severe cases

Treatment Duration

Treat for 5 days if clinical improvement occurs; extend only if symptoms have not improved within this timeframe. 1 This represents a major shift from traditional 7-14 day courses, as beta-lactam treatment is successful in 96% of patients with typical cellulitis. 1

When MRSA Coverage is NOT Needed

MRSA is an uncommon cause of typical cellulitis and coverage is usually unnecessary. 1 Beta-lactam monotherapy succeeds in 96% of cases, confirming that routine MRSA coverage provides no additional benefit. 1 Even in hospitals with high MRSA prevalence, MRSA remains an unusual cause of typical nonpurulent cellulitis. 1

When to Add MRSA Coverage

Add MRSA-active antibiotics ONLY when specific risk factors are present: 1

• Penetrating trauma or injection drug use
• Purulent drainage or exudate visible
• Evidence of MRSA infection elsewhere or known nasal colonization
• Systemic inflammatory response syndrome (SIRS) with fever, tachycardia, or hypotension
• Failure to respond to beta-lactam therapy after 48-72 hours

If MRSA coverage is indicated, use: 1

• Clindamycin 300-450 mg three times daily (covers both streptococci and MRSA, avoiding need for combination therapy)
• Trimethoprim-sulfamethoxazole 1-2 DS tablets twice daily PLUS a beta-lactam
• Doxycycline 100 mg twice daily PLUS a beta-lactam

Severe Infections Requiring Hospitalization

Admit patients with any of the following: 1

• SIRS criteria (fever, altered mental status, hemodynamic instability)
• Concern for necrotizing fasciitis (severe pain out of proportion to exam, skin anesthesia, rapid progression, gas in tissue, bullous changes)
• Severe immunocompromise or neutropenia
• Failure of outpatient treatment after 24-48 hours

For severe cellulitis with systemic toxicity, use broad-spectrum combination therapy: 1

• Vancomycin 15-20 mg/kg IV every 8-12 hours PLUS piperacillin-tazobactam 3.375-4.5 g IV every 6 hours
• Alternative: Linezolid 600 mg IV twice daily PLUS piperacillin-tazobactam
• Alternative: Vancomycin PLUS a carbapenem (meropenem 1 g IV every 8 hours)

Essential Adjunctive Measures

Elevation of the affected extremity hastens improvement by promoting drainage. 1 This is particularly important in patients with heart failure or chronic edema. 1

Treat predisposing conditions to reduce recurrence risk: 1

• Examine interdigital toe spaces for tinea pedis, fissuring, scaling, or maceration
• Address venous insufficiency, lymphedema, eczema, or obesity
• Treat toe web abnormalities

Consider systemic corticosteroids in non-diabetic adults: 1 Prednisone 40 mg daily for 7 days could be considered, though evidence is limited. However, avoid corticosteroids in diabetic patients. 1

Critical Pitfalls to Avoid

Do not routinely add MRSA coverage for typical nonpurulent cellulitis without specific risk factors. 1 Combination therapy with SMX-TMP plus cephalexin is no more efficacious than cephalexin alone in pure cellulitis without abscess, ulcer, or purulent drainage. 1

Do not extend treatment beyond 5 days automatically. 1 Only extend if clinical improvement has not occurred within the initial 5-day period.

Do not use doxycycline or trimethoprim-sulfamethoxazole as monotherapy for typical cellulitis. 1 These agents lack reliable activity against beta-hemolytic streptococci and must be combined with a beta-lactam. 1

Reassess within 24-48 hours for outpatients to ensure clinical improvement. 1 If no improvement occurs with appropriate first-line antibiotics, consider resistant organisms (particularly MRSA), cellulitis mimickers (venous stasis dermatitis, contact dermatitis, DVT), or underlying complications requiring drainage. 1, 2, 3