What are the first-line antibiotics for treating cellulitis?

First-Line Antibiotics for Cellulitis

For typical uncomplicated cellulitis, use beta-lactam monotherapy with cephalexin 500 mg four times daily for 5 days—MRSA coverage is unnecessary and provides no additional benefit. 1, 2

Standard Treatment Algorithm

Step 1: Confirm This is Typical Nonpurulent Cellulitis

• Look for expanding erythema, warmth, tenderness, and swelling WITHOUT purulent drainage, abscess, or penetrating trauma 1, 3
• If any fluctuance is present, obtain ultrasound to exclude abscess, as drainage—not antibiotics—is the primary treatment 1

Step 2: Choose Your Beta-Lactam (Pick One)

Preferred oral agents for typical cellulitis:

• Cephalexin 500 mg four times daily (most commonly recommended first-line) 1, 2
• Dicloxacillin 250-500 mg every 6 hours (excellent streptococcal and MSSA coverage) 1, 2
• Amoxicillin or penicillin (equally effective alternatives) 1, 2

For penicillin allergy:

• Clindamycin 300-450 mg four times daily (covers both streptococci and MRSA, avoiding need for combination therapy) 1, 2, 4

Step 3: Treat for 5 Days

• Stop at 5 days if clinical improvement has occurred 1, 2
• Extend treatment ONLY if symptoms have not improved within this timeframe 1, 2
• Traditional 7-14 day courses are outdated and unnecessary for uncomplicated cases 1

The Evidence Supporting Beta-Lactam Monotherapy

Beta-lactam therapy succeeds in 96% of typical cellulitis cases, confirming MRSA coverage is usually unnecessary. 1, 2 This high success rate exists because β-hemolytic streptococci and methicillin-sensitive S. aureus cause the vast majority of cases 2, 3. Even in settings with high community MRSA prevalence, MRSA remains an uncommon cause of typical nonpurulent cellulitis 1, 5.

Two high-quality randomized controlled trials definitively demonstrated that adding trimethoprim-sulfamethoxazole to cephalexin provides no additional benefit for uncomplicated cellulitis without abscess, ulcer, or purulent drainage 1, 6, 7. The 2017 JAMA trial showed clinical cure in 83.5% with combination therapy versus 85.5% with cephalexin alone—no significant difference 7.

When to Add MRSA Coverage (Specific Risk Factors Only)

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

• Penetrating trauma or injection drug use 1, 2
• Purulent drainage or exudate 1, 2
• Evidence of MRSA infection elsewhere or documented nasal MRSA colonization 1, 2
• Systemic inflammatory response syndrome (SIRS) with fever, hypotension, or altered mental status 1, 2

MRSA-active regimens when indicated:

• Clindamycin 300-450 mg four times daily (monotherapy covers both streptococci and MRSA) 1, 2, 4
• Trimethoprim-sulfamethoxazole PLUS cephalexin (combination required because TMP-SMX lacks reliable streptococcal activity) 1, 2
• Doxycycline 100 mg twice daily PLUS a beta-lactam (doxycycline alone is inadequate for streptococci) 1

Severe Cellulitis Requiring Hospitalization

Hospitalize and use IV antibiotics for:

• Systemic toxicity (SIRS, fever, hypotension, altered mental status) 1, 2
• Rapid progression or suspected necrotizing fasciitis 1, 2
• Severe immunocompromise or neutropenia 1
• Failed outpatient therapy 2

IV regimens for severe cellulitis:

• Vancomycin 15-20 mg/kg IV every 8-12 hours (first-line for hospitalized patients, A-I evidence) 1, 2
• Cefazolin 1-2 g IV every 8 hours (preferred IV beta-lactam if no MRSA risk factors) 1

For suspected necrotizing fasciitis or systemic toxicity, use broad-spectrum combination therapy:

• Vancomycin PLUS piperacillin-tazobactam 3.375-4.5 g IV every 6 hours 1, 2
• Alternative: Vancomycin PLUS a carbapenem (meropenem 1 g IV every 8 hours) 1, 2

Critical Pitfalls to Avoid

Do not reflexively add MRSA coverage simply because MRSA exists in your community. Even in high-prevalence settings, beta-lactam monotherapy remains successful in 96% of typical cellulitis cases 1, 2. The emergence of community-acquired MRSA has not changed the fact that β-hemolytic streptococci remain the predominant pathogen in nonpurulent cellulitis 3, 5.

Never use doxycycline or trimethoprim-sulfamethoxazole as monotherapy for typical cellulitis. These agents lack reliable activity against β-hemolytic streptococci and must be combined with a beta-lactam 1, 2.

Reassess at 48 hours if no improvement. Treatment failure should prompt consideration for resistant organisms, abscess requiring drainage, or cellulitis mimickers such as venous stasis dermatitis 1, 3, 5.

Adjunctive Measures That Accelerate Recovery

• Elevate the affected extremity to promote drainage and hasten improvement 1, 2
• Examine and treat interdigital toe spaces for tinea pedis, as this serves as a portal of entry and increases recurrence risk 1, 2
• Address predisposing conditions including edema, venous insufficiency, lymphedema, and obesity 1, 2
• Consider systemic corticosteroids (prednisone 40 mg daily for 7 days) in non-diabetic adults, though evidence is limited 1, 2