What is the first-line therapy for uncomplicated cellulitis in an otherwise healthy adult or child without MRSA risk?

First-Line Treatment for Uncomplicated Cellulitis

Beta-lactam monotherapy—specifically cephalexin 500 mg orally every 6 hours, dicloxacillin 250–500 mg every 6 hours, or amoxicillin—is the standard first-line treatment for typical uncomplicated cellulitis in otherwise healthy adults and children without MRSA risk factors, achieving a 96% clinical success rate. 1

Treatment Algorithm for Uncomplicated Cellulitis

Step 1: Confirm Nonpurulent Cellulitis

• Look for expanding erythema, warmth, tenderness, and swelling WITHOUT purulent drainage, exudate, or drainable abscess. 1, 2
• If any purulent drainage or fluctuance is present, this is NOT typical cellulitis and requires MRSA coverage. 1

Step 2: Select Appropriate Beta-Lactam Monotherapy

Recommended oral agents (choose one): 1

• Cephalexin 500 mg orally every 6 hours (four times daily) 1
• Dicloxacillin 250–500 mg orally every 6 hours 1
• Amoxicillin 500 mg orally three times daily 1
• Penicillin V 250–500 mg orally four times daily 1

For hospitalized patients requiring IV therapy: 1

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

Step 3: Treat for 5 Days

Treat for exactly 5 days if clinical improvement occurs (reduced warmth, tenderness, and erythema). 1 This duration is supported by high-quality randomized controlled trial evidence showing no difference in outcomes compared with 10-day courses. 1 Extend treatment only if symptoms have NOT improved within this 5-day timeframe. 1

Step 4: Essential Adjunctive Measures

• Elevate the affected extremity above heart level for at least 30 minutes three times daily to promote gravity drainage of edema. 1
• Examine interdigital toe spaces for tinea pedis, fissuring, or maceration and treat if present to reduce recurrence risk. 1
• Address predisposing conditions including venous insufficiency, lymphedema, and chronic edema. 1, 2

Why MRSA Coverage Is NOT Needed for Typical Cellulitis

MRSA is an uncommon cause of typical nonpurulent cellulitis, even in hospitals with high MRSA prevalence. 1 In the 15% of cellulitis cases where organisms are identified, most are β-hemolytic streptococci and methicillin-sensitive Staphylococcus aureus. 2 Beta-lactam monotherapy succeeds in 96% of typical cellulitis cases, confirming that routine MRSA coverage is unnecessary and represents overtreatment. 1

When to Add MRSA Coverage (Specific Risk Factors Only)

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

• 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 48–72 hours 1

If MRSA coverage is needed, use: 1

• 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 1

Critical Pitfalls to Avoid

Never use doxycycline or trimethoprim-sulfamethoxazole as monotherapy for typical cellulitis—these agents lack reliable activity against β-hemolytic streptococci, which are the primary pathogens in most cases. 1 Do not reflexively add MRSA coverage simply because the patient is hospitalized or because MRSA is prevalent in your community—this increases antibiotic resistance without improving outcomes in uncomplicated cases. 1 Do not extend treatment to 10–14 days based on residual erythema alone—some inflammation persists even after bacterial eradication, and traditional longer courses are no longer supported by evidence. 1

Pediatric Considerations

For children with uncomplicated cellulitis, use the same beta-lactam monotherapy approach: 1

• Cephalexin 25 mg/kg/day divided into four doses 3
• Amoxicillin 25–50 mg/kg/day divided into three doses 1

Avoid doxycycline in children younger than 8 years due to risk of permanent tooth discoloration and impaired bone growth. 1 Even in regions with endemic community-acquired MRSA, beta-lactams remain appropriate first-line empiric therapy for children with nondrained noncultured skin and soft-tissue infections. 4

Evidence Quality

The Infectious Diseases Society of America guidelines provide A-I level evidence (strong recommendation, high-quality evidence) supporting beta-lactam monotherapy as the standard of care for typical uncomplicated cellulitis. 1 This recommendation is further supported by a prospective, double-blind, randomized controlled trial demonstrating that adding MRSA coverage (trimethoprim-sulfamethoxazole) to cephalexin provides no additional benefit in nonpurulent cellulitis. 1, 5