What is the recommended oral antibiotic regimen for uncomplicated cellulitis?

Oral Antibiotic for Uncomplicated Cellulitis

For typical uncomplicated cellulitis, use cephalexin 500 mg four times daily or dicloxacillin 250-500 mg every 6 hours for 5 days—MRSA coverage is unnecessary and represents overtreatment in 96% of cases. 1, 2

First-Line Beta-Lactam Monotherapy

The Infectious Diseases Society of America establishes beta-lactam monotherapy as the standard of care for uncomplicated cellulitis, with a 96% success rate confirming that MRSA coverage is usually unnecessary. 1 This recommendation is based on the fact that β-hemolytic streptococci and methicillin-sensitive Staphylococcus aureus are the predominant pathogens in typical nonpurulent cellulitis. 1, 3

Recommended oral agents include: 1

• Cephalexin 500 mg four times daily (preferred first-line option) 2
• Dicloxacillin 250-500 mg every 6 hours 1
• Amoxicillin (appropriate dosing per clinical severity) 1
• Penicillin V 250-500 mg four times daily 1

For patients requiring broader coverage (such as bite-associated cellulitis), amoxicillin-clavulanate 875/125 mg twice daily provides single-agent coverage for both streptococci and common skin flora. 1, 4

Treatment Duration: 5 Days is Sufficient

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. A landmark randomized controlled trial demonstrated that 5 days of levofloxacin achieved 98% clinical resolution with no relapse by 28 days, identical to 10-day therapy. 5 The American College of Physicians and NICE guidelines both support 5-7 day courses for uncomplicated cases. 2

When to Add MRSA Coverage (Specific Criteria Only)

Do NOT routinely add MRSA coverage for typical nonpurulent cellulitis. 1 Even in areas with high community-acquired MRSA prevalence, combination therapy with trimethoprim-sulfamethoxazole plus cephalexin is no more efficacious than cephalexin alone in pure cellulitis without abscess, ulcer, or purulent drainage. 1, 6

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

• Penetrating trauma or injection drug use
• Purulent drainage or exudate
• Evidence of MRSA infection elsewhere or nasal MRSA colonization
• Systemic inflammatory response syndrome (SIRS)

When MRSA coverage is needed, use: 1

• Clindamycin 300-450 mg every 6 hours (covers both streptococci and MRSA, avoiding need for combination therapy—but only if local MRSA clindamycin resistance is <10%) 1
• Doxycycline 100 mg twice daily PLUS a beta-lactam (doxycycline lacks reliable streptococcal coverage and must never be used as monotherapy) 1
• Trimethoprim-sulfamethoxazole PLUS a beta-lactam 1

Critical Pitfalls to Avoid

Never use doxycycline or trimethoprim-sulfamethoxazole as monotherapy for typical cellulitis—their activity against beta-hemolytic streptococci is unreliable, and treatment failure rates increase significantly. 1 One retrospective study from Hawaii showed trimethoprim-sulfamethoxazole had higher success rates than cephalexin (91% vs 74%), but this was in a high MRSA-prevalence setting where many cases likely had unrecognized MRSA involvement. 7 However, the definitive randomized controlled trial demonstrated no benefit of adding trimethoprim-sulfamethoxazole to cephalexin for pure cellulitis without purulent drainage. 6

Do not reflexively add MRSA coverage simply because the patient is hospitalized—even in hospitals with high MRSA prevalence, typical cellulitis remains predominantly streptococcal. 1

Essential Adjunctive Measures

Beyond antibiotics, these interventions hasten recovery: 1, 2

• Elevate the affected extremity above heart level for at least 30 minutes three times daily to promote gravity drainage
• Examine and treat interdigital toe spaces for tinea pedis, fissuring, or maceration
• Address predisposing conditions including venous insufficiency, lymphedema, chronic edema, and obesity

Alternative Agents for Penicillin/Cephalosporin Allergy

For patients with true beta-lactam allergy: 1

• Clindamycin 300-450 mg every 6 hours (if local resistance <10%)
• Levofloxacin 500 mg daily (reserve for beta-lactam allergies; lacks reliable MRSA coverage)

Fluoroquinolones should be reserved for specific clinical scenarios due to antimicrobial stewardship concerns. 1

When to Hospitalize

Admit patients with any of the following: 1, 2

• Systemic inflammatory response syndrome (SIRS), fever >38°C, hypotension, or altered mental status
• Severe immunocompromise or neutropenia
• Signs suggesting necrotizing fasciitis (severe pain out of proportion to exam, skin anesthesia, rapid progression, bullous changes)
• Failure of outpatient therapy after 48 hours

For hospitalized patients requiring IV therapy, cefazolin 1-2 g IV every 8 hours is the preferred beta-lactam. 1 If MRSA coverage is needed, vancomycin 15-20 mg/kg IV every 8-12 hours is first-line. 1