What is the first-line treatment for cellulitis?

First-Line Treatment for Cellulitis

Beta-lactam monotherapy is the standard of care for typical uncomplicated cellulitis, with oral cephalexin 500 mg every 6 hours or dicloxacillin 250-500 mg every 6 hours as preferred first-line agents for 5 days. 1

Antibiotic Selection Algorithm

For Typical Nonpurulent Cellulitis (96% of Cases)

Use beta-lactam monotherapy only—MRSA coverage is unnecessary. 1 The Infectious Diseases Society of America confirms that beta-lactam treatment succeeds in 96% of patients, proving MRSA coverage is usually not needed. 1

Preferred oral options include: 1

• Cephalexin 500 mg every 6 hours (most commonly recommended first-line agent) 1, 2
• Dicloxacillin 250-500 mg every 6 hours 1, 2
• Amoxicillin 1
• Amoxicillin-clavulanate 875/125 mg twice daily 1
• Clindamycin 300-450 mg three times daily (if local MRSA resistance <10%) 1, 2

For hospitalized patients requiring IV therapy: 1

• Cefazolin 1-2 g IV every 8 hours (preferred IV beta-lactam) 1, 2
• Nafcillin (alternative for severe cases) 2

When to Add MRSA Coverage (Minority of Cases)

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 visible 1, 2
• Evidence of MRSA infection elsewhere or known nasal MRSA colonization 1, 2
• Systemic inflammatory response syndrome (SIRS): fever, hypotension, tachycardia, altered mental status 1, 2
• Failure to respond to beta-lactam therapy after 48 hours 1

MRSA-active oral regimens when indicated: 1

• Clindamycin 300-450 mg three times daily (monotherapy—covers both streptococci and MRSA) 1, 2
• Trimethoprim-sulfamethoxazole (TMP-SMX) PLUS a beta-lactam (cephalexin or amoxicillin) 1, 2
• Doxycycline 100 mg twice daily PLUS a beta-lactam 1

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

Treatment Duration

Treat for 5 days if clinical improvement occurs; extend only if symptoms have not improved within this timeframe. 1, 3, 2 Five-day courses are as effective as 10-day courses for uncomplicated cellulitis. 1, 2

Severe Cellulitis Requiring Broad-Spectrum Coverage

For patients with systemic toxicity, rapid progression, or suspected necrotizing fasciitis, use mandatory broad-spectrum combination therapy: 1

• Vancomycin 15-20 mg/kg IV every 8-12 hours PLUS piperacillin-tazobactam 3.375-4.5 g IV every 6 hours 1, 2
• Alternative: Linezolid 600 mg IV twice daily PLUS piperacillin-tazobactam 1
• Alternative: Vancomycin PLUS a carbapenem (meropenem 1 g IV every 8 hours) 1

Treatment duration for severe infections: 7-14 days guided by clinical response. 1

Essential Adjunctive Measures

Elevate the affected extremity to promote gravity drainage of edema and inflammatory substances—this hastens improvement. 1, 3, 2

Treat predisposing conditions: 1, 2

• Examine interdigital toe spaces for tinea pedis, fissuring, scaling, or maceration 2
• Address venous insufficiency, lymphedema, eczema, or obesity 1, 2

Consider systemic corticosteroids (prednisone 40 mg daily for 7 days) in non-diabetic adults only—evidence is limited but may hasten resolution. 1, 3 Never use corticosteroids in diabetic patients. 2

Hospitalization Criteria

Admit patients with any of the following: 1, 3, 2

• SIRS criteria (fever, altered mental status, hemodynamic instability) 2
• Concern for deeper or necrotizing infection 3, 2
• Severe immunocompromise or neutropenia 1
• Failure of outpatient treatment after 24-48 hours 2
• Poor adherence to outpatient therapy 3

Evidence Strength and Nuances

The recommendation for beta-lactam monotherapy is supported by A-I level evidence from the Infectious Diseases Society of America. 1 A landmark randomized controlled trial demonstrated that combination therapy with TMP-SMX plus cephalexin is no more efficacious than cephalexin alone in pure cellulitis without abscess, ulcer, or purulent drainage. 4 This confirms that adding MRSA coverage provides no additional benefit in typical cases. 1

However, one retrospective cohort study from Hawaii (a high MRSA-prevalence area) found higher success rates with TMP-SMX compared to cephalexin (91% vs 74%). 5 This divergent finding likely reflects a population with higher rates of purulent cellulitis or MRSA risk factors, not typical nonpurulent cellulitis. The guideline consensus remains that MRSA coverage should be reserved for specific risk factors, not used empirically. 1, 6

Common Pitfalls to Avoid

Do not routinely add MRSA coverage for typical cellulitis without specific risk factors—MRSA is an uncommon cause even in high-prevalence settings. 1, 2, 6

Do not extend treatment beyond 5 days automatically—only extend if clinical improvement has not occurred. 1, 3, 2

Do not use TMP-SMX or doxycycline as monotherapy—they must be combined with a beta-lactam for streptococcal coverage. 1, 2

Reassess within 24-48 hours for outpatients to ensure clinical improvement. 1, 2 If no improvement with appropriate first-line antibiotics, consider resistant organisms, cellulitis mimickers (venous stasis dermatitis, contact dermatitis, eczema), or underlying complications. 2, 6