What is the recommended treatment for a patient with uncomplicated cellulitis, considering potential penicillin allergy and severity of infection?

Treatment of Uncomplicated Cellulitis

For uncomplicated cellulitis, beta-lactam monotherapy with cephalexin 500 mg orally every 6 hours or dicloxacillin 250-500 mg every 6 hours for 5 days is the standard of care, achieving 96% success rates without requiring MRSA coverage. 1

First-Line Antibiotic Selection

Beta-lactam monotherapy is appropriate for typical nonpurulent cellulitis because MRSA is an uncommon cause even in high-prevalence settings. 1 The recommended oral agents include:

• Cephalexin 500 mg orally every 6 hours (preferred first-line agent with extensive clinical experience) 1, 2
• Dicloxacillin 250-500 mg every 6 hours (excellent streptococcal and MSSA coverage) 1, 3
• Amoxicillin (adequate streptococcal coverage for typical cases) 1
• Amoxicillin-clavulanate 875/125 mg twice daily (appropriate for bite-associated cellulitis) 1

These agents provide excellent coverage against beta-hemolytic streptococci (especially Streptococcus pyogenes) and methicillin-sensitive Staphylococcus aureus, which are the primary pathogens in most cases. 1, 2

Treatment Duration

Treat for exactly 5 days if clinical improvement occurs; extend only if symptoms have not improved within this timeframe. 1, 4 This recommendation is based on high-quality randomized controlled trial evidence showing that 5-day courses are as effective as 10-day courses for uncomplicated cellulitis. 4 Clinical improvement is defined as resolution of warmth and tenderness, improving erythema, and absence of fever. 1

When to Add MRSA Coverage

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

• Penetrating trauma or injection drug use 1
• Purulent drainage or exudate 1
• Known MRSA colonization or evidence of MRSA infection elsewhere 1
• Systemic inflammatory response syndrome (SIRS) 1

For patients requiring MRSA coverage, use:

• Clindamycin 300-450 mg orally every 6 hours (provides single-agent coverage for both streptococci and MRSA, avoiding need for combination therapy, but only if local MRSA clindamycin resistance is <10%) 1
• Trimethoprim-sulfamethoxazole 1-2 double-strength tablets twice daily PLUS a beta-lactam (cephalexin or dicloxacillin) 1
• Doxycycline 100 mg orally twice daily PLUS a beta-lactam (doxycycline must never be used as monotherapy due to unreliable streptococcal coverage) 1, 5

Critical evidence: Combination therapy with trimethoprim-sulfamethoxazole plus cephalexin is no more efficacious than cephalexin alone in pure cellulitis without abscess, ulcer, or purulent drainage. 1, 6

Management of Penicillin Allergy

For patients with penicillin allergy:

• Clindamycin 300-450 mg orally every 6 hours is the optimal choice, providing single-agent coverage for both streptococci and MRSA without requiring combination therapy (if local resistance <10%). 1
• Cephalexin 500 mg every 6 hours remains an option for patients with non-immediate penicillin allergy, as cross-reactivity between penicillins and cephalosporins is only 2-4%. 1
• Avoid cephalexin in patients with confirmed immediate-type amoxicillin allergy due to identical R1 side chains. 1

For patients allergic to both penicillins and sulfonamides (Bactrim):

• Clindamycin 300-450 mg orally every 6 hours for 5 days is the ideal option. 1
• Doxycycline alone is inadequate due to unreliable streptococcal coverage and should not be used as monotherapy. 1, 5

Indications for Hospitalization and IV Therapy

Hospitalize patients with any of the following: 1

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

For hospitalized patients with uncomplicated cellulitis without MRSA risk factors:

• Cefazolin 1-2 g IV every 8 hours (preferred IV beta-lactam) 1, 7
• Oxacillin 2 g IV every 6 hours (alternative) 1

For hospitalized patients requiring MRSA coverage:

• 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 (alternative, A-I evidence) 1
• Clindamycin 600 mg IV every 8 hours (if local resistance <10%, A-III evidence) 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

• Vancomycin 15-20 mg/kg IV every 8-12 hours PLUS piperacillin-tazobactam 3.375-4.5 g IV every 6 hours for 7-10 days 1
• Alternative combinations include vancomycin or linezolid PLUS a carbapenem, or ceftriaxone plus metronidazole 1

Warning signs requiring emergent surgical consultation: 1

• Severe pain out of proportion to examination findings 1
• Skin anesthesia 1
• Rapid progression or "wooden-hard" subcutaneous tissues 1
• Gas in tissue or bullous changes 1

Essential Adjunctive Measures

Elevation of the affected extremity is critical and often neglected:

• Elevate the limb above heart level for at least 30 minutes three times daily to promote gravity drainage of edema and inflammatory substances. 1, 8

Treat predisposing conditions to reduce recurrence risk: 1

• Examine interdigital toe spaces for tinea pedis, fissuring, scaling, or maceration and treat these conditions 1, 8
• Address venous insufficiency and lymphedema with compression stockings once acute infection resolves 1
• Manage chronic edema and obesity 1

Consider systemic corticosteroids in select patients:

• Prednisone 40 mg daily for 7 days could be considered in non-diabetic adults, though evidence is limited. 1

Common Pitfalls to Avoid

Do not routinely add MRSA coverage for typical cellulitis without specific risk factors, as this represents overtreatment and increases antibiotic resistance without improving outcomes. 1 Beta-lactam treatment is successful in 96% of patients, confirming that MRSA coverage is usually unnecessary. 1, 2

Do not use doxycycline or trimethoprim-sulfamethoxazole as monotherapy for typical cellulitis, as their activity against beta-hemolytic streptococci is unreliable. 1

Do not reflexively extend treatment to 7-10 days based on residual erythema alone, as some inflammation persists even after bacterial eradication. 1 Extending treatment to 10-14 days based on tradition rather than evidence is a common error that increases antibiotic resistance without improving outcomes. 1

Reassess patients within 24-48 hours to verify clinical response, as treatment failure rates of 21% have been reported with some oral regimens. 1, 8