What is the recommended treatment for cellulitis?

Treatment of Cellulitis

First-Line Antibiotic Therapy

Beta-lactam monotherapy is the standard of care for typical uncomplicated cellulitis, with a 96% success rate, and MRSA coverage is unnecessary in most cases. 1, 2

Recommended Oral Regimens for Uncomplicated Cellulitis

• Cephalexin 500 mg four times daily for 5 days 1
• Dicloxacillin 250-500 mg every 6 hours for 5 days 1, 2
• Amoxicillin (standard dosing) for 5 days 1, 2
• Penicillin V 250-500 mg four times daily for 5 days 1
• Clindamycin 300-450 mg every 6 hours for 5 days (covers both streptococci and MRSA, useful for penicillin allergy) 1, 2

Treatment Duration

Treat for exactly 5 days if clinical improvement occurs; extend only if symptoms have not improved within this timeframe. 1, 2 This represents a major shift from traditional 7-14 day courses and is supported by high-quality randomized controlled trial evidence. 1

When to Add MRSA Coverage

Do NOT routinely add MRSA coverage for typical nonpurulent cellulitis. 1, 2 MRSA is an uncommon cause of typical cellulitis even in high-prevalence settings. 1, 3

Specific Indications for MRSA Coverage

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

• Penetrating trauma or injection drug use 1
• Purulent drainage or exudate 1
• Known MRSA colonization or prior MRSA infection 1
• Systemic inflammatory response syndrome (SIRS) 1
• Failure to respond to beta-lactam therapy after 48 hours 1

MRSA-Active Regimens

When MRSA coverage is needed: 1

• Clindamycin monotherapy 300-450 mg every 6 hours (covers both streptococci and MRSA, but only if local resistance <10%) 1, 2
• Trimethoprim-sulfamethoxazole PLUS a beta-lactam (e.g., cephalexin) 1
• Doxycycline 100 mg twice daily PLUS a beta-lactam 1

Critical pitfall: Never use doxycycline or trimethoprim-sulfamethoxazole as monotherapy for cellulitis—their activity against beta-hemolytic streptococci is unreliable. 1, 2

Inpatient/IV Therapy

Indications for Hospitalization

Hospitalize if ANY of the following are present: 1, 2

• Systemic inflammatory response syndrome (SIRS): fever >38°C, tachycardia >90 bpm, tachypnea >24 rpm 1
• Hypotension or hemodynamic instability 1, 2
• Altered mental status or confusion 1, 2
• Severe immunocompromise or neutropenia 1, 2
• Concern for necrotizing fasciitis or deeper infection 1, 2

IV Antibiotic Selection for Uncomplicated Cellulitis Requiring Hospitalization

For typical cellulitis without MRSA risk factors: 1

• Cefazolin 1-2 g IV every 8 hours (preferred) 1
• Oxacillin 2 g IV every 6 hours (alternative) 1

For complicated cellulitis or when MRSA coverage is needed: 1, 2

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

Severe Cellulitis with Systemic Toxicity 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: Linezolid 600 mg IV twice daily PLUS piperacillin-tazobactam 1
• Alternative: Vancomycin PLUS a carbapenem (meropenem 1 g IV every 8 hours) 1
• Alternative: Vancomycin PLUS ceftriaxone 2 g IV daily and metronidazole 500 mg IV every 8 hours 1

Duration for severe infections: 7-14 days guided by clinical response, NOT the standard 5 days. 1

Special Situations

Bite-Associated Cellulitis (Human or Animal)

Amoxicillin-clavulanate (Augmentin) 875/125 mg twice daily as monotherapy provides single-agent coverage for polymicrobial oral flora. 1 Do NOT add trimethoprim-sulfamethoxazole to this regimen. 1

Penicillin Allergy

• Clindamycin 300-450 mg every 6 hours is the optimal choice (covers both streptococci and MRSA) 1
• Levofloxacin 500 mg daily can be used but should be reserved for beta-lactam allergies to minimize resistance 1

Cephalosporin Allergy

• Penicillin V 250-500 mg four times daily (if no cross-reactivity concern) 1
• Clindamycin 300-450 mg every 6 hours 1
• Carbapenems can be safely used in cephalosporin-allergic patients 1

Essential Adjunctive Measures

These are often neglected but critical for treatment success: 1, 2

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

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: 1, 2

• Prophylactic penicillin V 250 mg orally twice daily 1, 2
• Prophylactic erythromycin 250 mg orally twice daily 1, 2
• Intramuscular benzathine penicillin (alternative) 2

Critical Pitfalls to Avoid

• Do NOT reflexively add MRSA coverage simply because the patient is hospitalized or in a high-prevalence area—beta-lactam monotherapy succeeds in 96% of typical cases 1, 3, 4
• Do NOT use doxycycline or trimethoprim-sulfamethoxazole as monotherapy—they lack reliable streptococcal coverage 1, 2
• Do NOT continue ineffective antibiotics beyond 48 hours—progression despite appropriate therapy indicates resistant organisms or deeper infection 1
• Do NOT miss necrotizing fasciitis warning signs: severe pain out of proportion to exam, skin anesthesia, rapid progression, gas in tissue, bullous changes, or "wooden-hard" subcutaneous tissues—these require emergent surgical consultation 1
• Do NOT forget to assess for abscess with ultrasound if there is any clinical uncertainty—purulent collections require incision and drainage, not antibiotics alone 1

Reassessment

Mandatory reassessment in 24-48 hours to verify clinical response, as treatment failure rates of 21% have been reported with some regimens. 1 If spreading despite appropriate antibiotics, reassess for MRSA risk factors, necrotizing infection, or misdiagnosis. 1