What is the recommended treatment for skin cellulitis?

Treatment for Skin Cellulitis

For typical uncomplicated cellulitis, beta-lactam monotherapy with oral cephalexin, dicloxacillin, or amoxicillin for 5 days is the standard of care, achieving 96% success rates without requiring MRSA coverage. 1

First-Line Antibiotic Selection

Standard Oral Regimens for Uncomplicated Cellulitis

• Cephalexin 500 mg orally four times daily is the preferred first-line agent, providing effective coverage against streptococci and methicillin-sensitive Staphylococcus aureus 1, 2
• Dicloxacillin 250-500 mg orally every 6 hours is equally effective as first-line therapy 1, 2
• Amoxicillin alone provides adequate streptococcal coverage for typical nonpurulent cellulitis 1
• Amoxicillin-clavulanate 875/125 mg twice daily is appropriate for bite-associated cellulitis or when broader coverage is desired 1

Intravenous Options for Hospitalized Patients

• Cefazolin 1-2 g IV every 8 hours is the preferred IV beta-lactam for hospitalized patients with uncomplicated cellulitis 1, 2
• Nafcillin 2 g IV every 6 hours or oxacillin 2 g IV every 6 hours are alternatives 1

Treatment Duration

Treat for exactly 5 days if clinical improvement occurs; extend only if symptoms have not improved within this timeframe. 1, 2, 3 This represents a major shift from traditional 7-14 day courses, with high-quality randomized controlled trial evidence demonstrating that 5-day courses are as effective as 10-day courses for uncomplicated cellulitis 1, 4.

When to Add MRSA Coverage

MRSA is an uncommon cause of typical cellulitis, even in high-prevalence settings, and routine coverage is unnecessary 1, 5, 6. Add MRSA-active antibiotics ONLY when specific risk factors are present: 1, 2, 3

• Penetrating trauma or injection drug use 1, 2, 3
• Purulent drainage or exudate 1, 2, 3
• Evidence of MRSA infection elsewhere or known nasal MRSA colonization 1, 2, 3
• Systemic inflammatory response syndrome (SIRS): fever >38°C, tachycardia >90 bpm, hypotension, or altered mental status 1, 2
• Failure to respond to beta-lactam therapy after 48-72 hours 1, 7

MRSA-Active Regimens When Indicated

For outpatients requiring MRSA coverage:

• Clindamycin 300-450 mg orally every 6 hours provides single-agent coverage for both streptococci and MRSA (use only if local resistance <10%) 1, 2, 7
• Trimethoprim-sulfamethoxazole (TMP-SMX) 1-2 double-strength tablets twice daily PLUS a beta-lactam (cephalexin, amoxicillin, or penicillin) 1, 2, 7
• Doxycycline 100 mg orally twice daily PLUS a beta-lactam 1, 2

Critical pitfall: Never use TMP-SMX or doxycycline as monotherapy for typical cellulitis, as their activity against beta-hemolytic streptococci is unreliable 1, 7.

For hospitalized patients with complicated cellulitis:

• Vancomycin 15-20 mg/kg IV every 8-12 hours is first-line (A-I evidence) 1, 8
• Linezolid 600 mg IV twice daily is equally effective (A-I evidence) 1
• Daptomycin 4 mg/kg IV once daily (A-I evidence) 1
• Clindamycin 600 mg IV every 8 hours if local resistance <10% 1

Severe Cellulitis with Systemic Toxicity

For patients with signs of systemic toxicity, rapid progression, or suspected necrotizing fasciitis, mandatory broad-spectrum combination therapy is required: 1, 2

• Vancomycin 15-20 mg/kg IV every 8-12 hours PLUS piperacillin-tazobactam 3.375-4.5 g IV every 6 hours 1
• Alternative combinations: vancomycin PLUS a carbapenem (meropenem 1 g IV every 8 hours) OR vancomycin PLUS ceftriaxone 2 g IV daily and metronidazole 500 mg IV every 8 hours 1
• Duration: 7-14 days guided by clinical response 1

Warning signs requiring emergent surgical consultation: severe pain out of proportion to examination, skin anesthesia, rapid progression, gas in tissue, bullous changes, or "wooden-hard" subcutaneous tissues 1.

Penicillin Allergy Considerations

• Clindamycin 300-450 mg orally every 6 hours is the optimal choice for patients allergic to both penicillins and sulfonamides, providing single-agent coverage without requiring combination therapy 1, 2
• Cefuroxime 500 mg orally twice daily can be used in patients with cephalosporin allergy but not penicillin allergy, as cross-reactivity is less common than historically believed 1
• Levofloxacin 500 mg daily for 5 days is effective but should be reserved for beta-lactam allergies due to antimicrobial stewardship concerns 1

Essential Adjunctive Measures

These interventions are frequently neglected but significantly impact outcomes:

• Elevate the affected extremity above heart level for at least 30 minutes three times daily to promote gravity drainage of edema 1, 2, 3
• Examine interdigital toe spaces carefully for tinea pedis, fissuring, scaling, or maceration; treating these eradicates colonization and reduces recurrence risk 1, 2
• Treat predisposing conditions: venous insufficiency (compression stockings), lymphedema, chronic edema, eczema, obesity 1, 2, 3
• Consider systemic corticosteroids (prednisone 40 mg daily for 7 days) in non-diabetic adults to reduce inflammation, though evidence is limited 1, 2

Hospitalization Criteria

Admit patients with any of the following: 1, 2

• SIRS criteria (fever, tachycardia, tachypnea, abnormal WBC)
• Hypotension or hemodynamic instability
• Altered mental status or confusion
• Severe immunocompromise or neutropenia
• Concern for deeper or necrotizing infection
• Failure of outpatient treatment after 24-48 hours

Monitoring and Treatment Failure

• Reassess within 24-48 hours for outpatients to verify clinical improvement 1
• If no improvement with appropriate first-line antibiotics, consider: resistant organisms (add MRSA coverage), abscess requiring drainage (obtain ultrasound), deep vein thrombosis mimicking cellulitis, or necrotizing infection 1, 7
• Blood cultures are positive in only 5% of cases and unnecessary for typical cellulitis; obtain only in patients with malignancy, severe systemic features, neutropenia, or severe immunodeficiency 1, 6

Prevention of Recurrent Cellulitis

Annual recurrence rates are 8-20% in patients with previous cellulitis 1. For patients with 3-4 episodes per year despite treating predisposing factors:

• Prophylactic penicillin V 250 mg orally twice daily or erythromycin 250 mg orally twice daily for 4-52 weeks 1, 3
• Intramuscular benzathine penicillin every 2-4 weeks 1
• Address underlying venous insufficiency and lymphedema with compression stockings once acute infection resolves 1, 3

Common Pitfalls to Avoid

• Do not routinely add MRSA coverage for typical cellulitis without specific risk factors—this represents overtreatment and increases antibiotic resistance 1, 5
• Do not extend treatment beyond 5 days automatically—only extend if clinical improvement has not occurred 1
• Do not use combination therapy (cephalexin plus TMP-SMX) for pure cellulitis without abscess, ulcer, or purulent drainage, as it provides no additional benefit 1, 5
• Do not delay surgical consultation if any signs of necrotizing infection are present, as these progress rapidly 1