What is the first-line outpatient therapy for uncomplicated, non-purulent cellulitis?

First-Line Treatment for Non-Purulent Cellulitis

Beta-lactam monotherapy—specifically cephalexin 500 mg orally every 6 hours, dicloxacillin 250-500 mg every 6 hours, or amoxicillin—is the standard of care for typical non-purulent cellulitis, achieving 96% clinical success without MRSA coverage. 1

Recommended Oral Beta-Lactam Regimens

The Infectious Diseases Society of America establishes beta-lactam monotherapy as first-line treatment for uncomplicated, non-purulent cellulitis because β-hemolytic streptococci (especially Streptococcus pyogenes) and methicillin-sensitive Staphylococcus aureus are the primary pathogens in typical cases. 1, 2, 3

Preferred oral agents include:

• Cephalexin 500 mg orally every 6 hours (four times daily) for 5 days 1
• Dicloxacillin 250-500 mg orally every 6 hours for 5 days 1
• Amoxicillin (standard dosing) for 5 days 1
• Penicillin V 250-500 mg orally four times daily for 5 days 1
• Amoxicillin-clavulanate 875/125 mg twice daily for broader coverage 1

Treatment Duration

Treat for exactly 5 days if clinical improvement occurs (reduced warmth, tenderness, and erythema); extend only if symptoms have not improved within this timeframe. 1 This recommendation is supported by high-quality randomized controlled trial evidence showing that 5-day courses are as effective as 10-day courses for uncomplicated cellulitis. 1 Traditional 7-14 day regimens are no longer necessary and represent overtreatment. 1

When MRSA Coverage Is NOT Needed

MRSA is an uncommon cause of typical non-purulent cellulitis, even in hospitals with high MRSA prevalence. 1 Beta-lactam monotherapy succeeds in 96% of cases, confirming that routine MRSA coverage is unnecessary. 1, 4 Adding MRSA-active antibiotics to beta-lactam therapy provides no additional benefit in typical cases. 1

When to Add MRSA Coverage

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

• Penetrating trauma or injection drug use 1
• Purulent drainage or exudate (visible) 1
• Known MRSA colonization or prior MRSA infection 1
• Systemic inflammatory response syndrome (SIRS) 1
• Failure to respond to beta-lactam therapy after 48-72 hours 1

If MRSA coverage is required, use:

• Clindamycin 300-450 mg orally every 6 hours (provides single-agent coverage for both streptococci and MRSA, but only if local MRSA clindamycin resistance <10%) 1
• Trimethoprim-sulfamethoxazole 1-2 double-strength tablets twice daily PLUS a beta-lactam (cephalexin or amoxicillin) 1
• Doxycycline 100 mg orally twice daily PLUS a beta-lactam (for patients >8 years old; never use doxycycline as monotherapy because it lacks reliable streptococcal coverage) 1

Intravenous Options for Hospitalized Patients

For patients requiring hospitalization without MRSA risk factors, the preferred IV beta-lactam is cefazolin 1-2 g IV every 8 hours, with oxacillin or nafcillin as alternatives. 1 For severe cellulitis with systemic toxicity or suspected necrotizing fasciitis, mandatory broad-spectrum combination therapy includes vancomycin 15-20 mg/kg IV every 8-12 hours PLUS piperacillin-tazobactam 3.375-4.5 g IV every 6 hours. 1

Essential Adjunctive Measures

Elevation of the affected extremity above heart level for at least 30 minutes three times daily hastens improvement by promoting gravity drainage of edema and inflammatory substances. 1 Examine interdigital toe spaces for tinea pedis, fissuring, scaling, or maceration, and treat these conditions to eradicate colonization and reduce recurrent infection. 1 Address predisposing conditions including venous insufficiency, lymphedema, and chronic edema. 1

Common Pitfalls to Avoid

• Do not reflexively add MRSA coverage for typical non-purulent cellulitis without specific risk factors—this represents overtreatment and increases antibiotic resistance without improving outcomes. 1
• Do not use doxycycline or trimethoprim-sulfamethoxazole as monotherapy for typical cellulitis, as their activity against β-hemolytic streptococci is unreliable. 1
• Do not extend treatment to 10-14 days based on tradition rather than evidence—this increases antibiotic resistance without improving outcomes in uncomplicated cases. 1
• Reassess patients within 24-48 hours to verify clinical response, as treatment failure rates of 21% have been reported with some oral regimens. 1