What is the first-line treatment for uncomplicated cellulitis?

First-Line Treatment for Uncomplicated Cellulitis

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

Recommended Oral Beta-Lactam Agents

The following oral antibiotics provide excellent coverage against streptococci and methicillin-sensitive S. aureus, which cause the majority of uncomplicated cellulitis cases:

• Cephalexin 500 mg four times daily 1
• Dicloxacillin 250-500 mg every 6 hours 1
• Amoxicillin (standard dosing) 1
• Penicillin V 250-500 mg four times daily 1
• Amoxicillin-clavulanate 875/125 mg twice daily (particularly for bite-associated cellulitis) 1

Treatment duration is 5 days if clinical improvement occurs, extending only if symptoms have not improved within this timeframe. 1, 2 This represents a significant departure from traditional 7-14 day courses and is supported by high-quality randomized controlled trial evidence showing 98% clinical resolution with 5-day courses. 2

When Beta-Lactam Monotherapy is Appropriate

Use simple beta-lactam monotherapy for cellulitis that is:

• Nonpurulent (no drainage, exudate, or abscess) 1
• Without systemic toxicity (no fever, hypotension, altered mental status) 1
• Lacking MRSA risk factors (see below) 1

Even in hospitals with high MRSA prevalence, typical nonpurulent cellulitis rarely involves MRSA, and reflexively adding MRSA coverage represents overtreatment. 1

When to Add MRSA Coverage

Add MRSA-active antibiotics ONLY when specific risk factors are present: 1, 3

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

For MRSA coverage, use:

• Clindamycin 300-450 mg orally every 6 hours (monotherapy covering both streptococci and MRSA, but only if local resistance <10%) 1
• Trimethoprim-sulfamethoxazole PLUS a beta-lactam (combination required because TMP-SMX lacks reliable streptococcal coverage) 1
• Doxycycline 100 mg twice daily PLUS a beta-lactam (combination required because doxycycline has unreliable activity against beta-hemolytic streptococci) 1

Critical Pitfalls to Avoid

Never use doxycycline or TMP-SMX as monotherapy for typical cellulitis—their activity against beta-hemolytic streptococci is unreliable, and streptococci are the primary pathogens in most cases. 1 Combination therapy with SMX-TMP plus cephalexin provides no additional benefit over cephalexin alone in pure cellulitis without abscess or purulent drainage. 1

Do not routinely add MRSA coverage for typical nonpurulent cellulitis—this increases antibiotic resistance and adverse effects without improving outcomes. 1 Even with rising community-acquired MRSA rates, coverage is generally not recommended for nonpurulent cellulitis. 4

Intravenous Options for Hospitalized Patients

For uncomplicated cellulitis requiring hospitalization (due to inability to take oral medications or need for observation), use:

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

Transition to oral therapy once clinical improvement is demonstrated, typically after 4 days of IV treatment. 1

Essential Adjunctive Measures

Elevation of the affected extremity hastens improvement by promoting gravitational drainage of edema and inflammatory substances—this is critical and often neglected. 1

Treat predisposing conditions to reduce recurrence risk (annual recurrence rates are 8-20%): 1

• Examine interdigital toe spaces for tinea pedis, fissuring, or maceration and treat aggressively 1
• Address venous insufficiency with compression stockings once acute infection resolves 1
• Manage chronic edema and lymphedema 1

Severe Cellulitis Requiring Broad-Spectrum Coverage

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

• 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 600 mg IV twice daily PLUS piperacillin-tazobactam 1

These severe infections require 7-14 days of therapy and emergent surgical consultation if necrotizing infection is suspected. 1

Penicillin Allergy Considerations

For patients with penicillin allergy:

• Clindamycin 300-450 mg every 6 hours (covers both streptococci and MRSA if local resistance <10%) 1
• Levofloxacin 500 mg daily (reserve for beta-lactam allergies; 5-day course is as effective as 10 days) 1, 2

The evidence strongly supports that in the 85% of cellulitis cases where organisms cannot be cultured, and in the 15% where they are identified, beta-hemolytic streptococci and methicillin-sensitive S. aureus predominate. 3, 4 This microbiological reality justifies the beta-lactam monotherapy approach and explains why MRSA coverage adds no benefit in typical cases. 1