What are the first-line antibiotics for treating cellulitis?

First-Line Antibiotics for Cellulitis

For typical uncomplicated cellulitis, cephalexin 500 mg four times daily for 5 days is the first-line treatment, as beta-lactam monotherapy is successful in 96% of cases and MRSA coverage is unnecessary. 1, 2

Standard Beta-Lactam Monotherapy

The Infectious Diseases Society of America and American College of Physicians establish beta-lactam antibiotics as the standard of care for typical nonpurulent cellulitis because β-hemolytic streptococci and methicillin-sensitive Staphylococcus aureus cause the vast majority of cases. 1, 2

Recommended oral beta-lactam options include:

• Cephalexin 500 mg four times daily (preferred first-line agent) 2
• Penicillin or amoxicillin (equally effective alternatives) 1, 2
• Dicloxacillin 250 mg every 6 hours for moderate infections 1
• Amoxicillin-clavulanate 875/125 mg twice daily (reasonable for bite-associated cellulitis) 1
• Cefuroxime 500 mg twice daily 1

Treatment Duration

Treat for 5 days if clinical improvement occurs; extend only if symptoms have not improved within this timeframe. 1, 2 Traditional 7-14 day courses are no longer necessary for uncomplicated cases. 1

Penicillin-Allergic Patients

Clindamycin 300-450 mg four times daily is the recommended alternative for penicillin-allergic patients. 2, 3 This agent provides coverage for both streptococci and MRSA, making it particularly useful when allergy limits beta-lactam options. 1, 2

When MRSA Coverage IS Required

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

• Penetrating trauma or injection drug use 1, 2
• Purulent drainage or exudate 1, 2
• Evidence of MRSA infection elsewhere or nasal MRSA colonization 1, 2
• Systemic inflammatory response syndrome (SIRS) 1, 2

For cellulitis requiring MRSA coverage, use:

• Clindamycin 300-450 mg four times daily (monotherapy covering both streptococci and MRSA) 1, 2
• Trimethoprim-sulfamethoxazole (TMP-SMX) PLUS cephalexin (combination therapy) 1, 2
• Doxycycline 100 mg twice daily PLUS a beta-lactam (combination therapy) 1

Critical Evidence on MRSA Coverage

A randomized controlled trial demonstrated that adding TMP-SMX to cephalexin provided no benefit over cephalexin alone for pure cellulitis without abscess: 85% cure rate with combination therapy versus 82% with cephalexin alone (not statistically significant). 4 This confirms guideline recommendations that MRSA coverage is unnecessary for typical nonpurulent cellulitis. 1, 2

However, one retrospective study from Hawaii (high MRSA prevalence area) showed TMP-SMX had higher success rates than cephalexin (91% vs 74%), but this study included patients with purulent infections and abscess drainage, making it less applicable to pure cellulitis. 5 The key distinction is that pure nonpurulent cellulitis does not require MRSA coverage, even in high-prevalence settings. 1, 2

Common Pitfalls to Avoid

Do not reflexively add MRSA coverage simply because community-acquired MRSA is prevalent in your area—MRSA is an uncommon cause of typical nonpurulent cellulitis. 1, 2 Beta-lactam monotherapy succeeds in 96% of typical cellulitis cases. 1, 2

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

Distinguish cellulitis from purulent collections (abscesses, furuncles): purulent collections require incision and drainage as primary treatment, with antibiotics playing a subsidiary role. 1 If clinical uncertainty exists, obtain ultrasound to assess for abscess. 1

Adjunctive Measures

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 addressing it reduces recurrence risk. 1, 2

Consider systemic corticosteroids (prednisone 40 mg daily for 7 days) in non-diabetic adults, though evidence is limited. 1, 2

Severe Infections Requiring Hospitalization

Hospitalize patients with: 1, 2

• Systemic inflammatory response syndrome (SIRS), fever, hypotension, or altered mental status 1, 2
• Severe immunocompromise or neutropenia 1
• Signs of necrotizing fasciitis (severe pain out of proportion to exam, skin anesthesia, rapid progression, gas in tissue, bullous changes) 1

For severe cellulitis with systemic toxicity, use vancomycin 15-20 mg/kg IV every 8-12 hours PLUS piperacillin-tazobactam 3.375-4.5 grams IV every 6 hours. 1, 2 Alternative MRSA-active IV agents include linezolid 600 mg IV twice daily, daptomycin 4 mg/kg IV once daily, or clindamycin 600 mg IV three times daily (if local resistance <10%). 1