What is the appropriate oral antibiotic regimen for an otherwise healthy adult with uncomplicated non‑purulent cellulitis, and how should therapy be modified if the patient has risk factors for community‑associated methicillin‑resistant Staphylococcus aureus (MRSA)?

Oral Antibiotic Treatment for Uncomplicated Cellulitis

First-Line Therapy: Beta-Lactam Monotherapy

For otherwise healthy adults with typical non-purulent cellulitis, beta-lactam monotherapy—specifically cephalexin 500 mg orally four times daily, dicloxacillin 250-500 mg every 6 hours, or amoxicillin—is the standard of care and achieves 96% clinical success. 1

Recommended Oral Beta-Lactam Regimens

• Cephalexin 500 mg orally every 6 hours (four times daily) provides excellent coverage against beta-hemolytic streptococci and methicillin-sensitive Staphylococcus aureus, the primary pathogens in typical cellulitis 1, 2
• Dicloxacillin 250-500 mg orally every 6 hours is equally effective for streptococcal and MSSA coverage 1, 3
• Amoxicillin is an acceptable alternative beta-lactam option 1
• Penicillin V 250-500 mg orally four times daily provides excellent streptococcal coverage 1

Treatment Duration

• Treat for exactly 5 days if clinical improvement occurs (resolution of warmth and tenderness, improving erythema, no fever) 1
• Extend treatment only if symptoms have not improved within this 5-day timeframe 1
• Traditional 7-14 day courses are no longer necessary for uncomplicated cases 1

When to Add MRSA Coverage

MRSA coverage should be added ONLY when specific risk factors are present, as MRSA is an uncommon cause of typical non-purulent cellulitis even in high-prevalence settings. 1, 4

Specific MRSA Risk Factors Requiring Coverage

• Penetrating trauma or injection drug use 1, 4
• Purulent drainage or exudate visible on examination 1, 4
• Known MRSA colonization or prior MRSA infection 1, 4
• Systemic inflammatory response syndrome (SIRS)—fever >38°C, tachycardia >90 bpm, tachypnea >24 rpm 1, 4
• Failure to respond to beta-lactam therapy after 48-72 hours 1, 4

Oral Regimens When MRSA Coverage Is Needed

Option 1: Clindamycin Monotherapy (Preferred)

Clindamycin 300-450 mg orally every 6 hours provides single-agent coverage for both streptococci and MRSA, eliminating the need for combination therapy. 1, 4

• Use ONLY if local MRSA clindamycin resistance rates are <10% 1, 4
• This is the optimal choice for penicillin-allergic patients requiring MRSA coverage 1

Option 2: Combination Therapy with TMP-SMX or Doxycycline

When clindamycin resistance exceeds 10%, use trimethoprim-sulfamethoxazole (TMP-SMX) 1-2 double-strength tablets twice daily PLUS a beta-lactam (cephalexin or amoxicillin). 1, 4

• Alternative: Doxycycline 100 mg orally twice daily PLUS a beta-lactam 1, 4
• Critical pitfall: Never use TMP-SMX or doxycycline as monotherapy for typical cellulitis—these agents lack reliable activity against beta-hemolytic streptococci 1, 4

Contraindications to Doxycycline

• Never use in children younger than 8 years (risk of permanent tooth discoloration and impaired bone growth) 1
• Avoid in pregnant women (pregnancy category D) 1

Clinical Algorithm for Antibiotic Selection

Step 1: Assess for Purulent vs. Non-Purulent Cellulitis

• Non-purulent cellulitis (no drainage, no abscess): Start beta-lactam monotherapy 1, 2
• Purulent cellulitis (visible drainage or associated abscess): Add MRSA coverage 1, 4

Step 2: Evaluate MRSA Risk Factors

• No risk factors present: Beta-lactam monotherapy (cephalexin, dicloxacillin, or amoxicillin) for 5 days 1
• One or more risk factors present: Add MRSA coverage with clindamycin monotherapy OR combination therapy 1, 4

Step 3: Reassess at 48-72 Hours

• Clinical improvement (reduced warmth, tenderness, erythema): Complete 5-day course 1
• No improvement or worsening: Switch to MRSA-active regimen if not already prescribed, or consider hospitalization 1, 4

Common Pitfalls to Avoid

• Do not reflexively add MRSA coverage to all cellulitis cases—this represents overtreatment and increases antibiotic resistance without improving outcomes in the 96% of cases caused by streptococci or MSSA 1, 4
• Do not use doxycycline or TMP-SMX as monotherapy—this misses streptococcal pathogens in the vast majority of typical cellulitis cases 1, 4
• Do not extend treatment to 10-14 days based on residual erythema alone—some inflammation persists even after bacterial eradication 1
• Do not use beta-lactams alone when MRSA is suspected or confirmed—they have no activity against methicillin-resistant organisms 4

Adjunctive Measures

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

Indications for Hospitalization

• Systemic inflammatory response syndrome (SIRS), fever, hypotension, or altered mental status 1
• Severe immunocompromise or neutropenia 1
• Signs of necrotizing fasciitis—severe pain out of proportion to examination, skin anesthesia, rapid progression, "wooden-hard" subcutaneous tissues 1