What is the recommended management of cellulitis in a healthy adult, including first‑line oral therapy for non‑purulent infection, alternatives for penicillin allergy, MRSA‑covering regimens for purulent infection, and intravenous treatment for severe disease?

Management of Cellulitis in Healthy Adults

First-Line Oral Therapy for Non-Purulent Cellulitis

Beta-lactam monotherapy is the standard of care for typical uncomplicated cellulitis, achieving 96% clinical success because MRSA is an uncommon cause even in high-prevalence settings. 1

Recommended Oral Agents (Choose One)

• Cephalexin 500 mg orally every 6 hours 1
• Dicloxacillin 250-500 mg orally every 6 hours 1
• Amoxicillin (standard dosing) 1
• Amoxicillin-clavulanate 875/125 mg twice daily 1

Treatment Duration

Treat for exactly 5 days if warmth, tenderness, and erythema are improving and the patient is afebrile; extend only if these symptoms have not improved within this timeframe. 1 High-quality randomized controlled trial evidence confirms that 5-day courses are as effective as 10-day courses for uncomplicated cellulitis. 1

Critical Evidence Supporting Beta-Lactam Monotherapy

A randomized, double-blind, placebo-controlled trial demonstrated that adding trimethoprim-sulfamethoxazole to cephalexin provided no additional benefit for non-purulent cellulitis (85% cure rate with combination vs. 82% with cephalexin alone, p=0.66). 2 This confirms that routine MRSA coverage is unnecessary for typical cellulitis. 1, 2

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Alternatives for Penicillin Allergy

For Non-Immediate Penicillin Allergy

Cephalexin remains acceptable because cross-reactivity between penicillins and cephalosporins is only 2-4%, primarily based on R1 side chain similarity rather than the beta-lactam ring. 1 However, avoid cephalexin in patients with confirmed immediate-type amoxicillin allergy due to identical R1 side chains. 1

For True Penicillin Allergy

Clindamycin 300-450 mg orally every 6 hours for 5 days is the preferred alternative, providing single-agent coverage for both streptococci and MRSA—but use only if local MRSA clindamycin resistance rates are <10%. 1

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MRSA-Covering Regimens for Purulent Infection

When to Add MRSA Coverage

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

• Purulent drainage or exudate (visible at the infection site) 1
• Penetrating trauma or injection drug use 1
• Known MRSA colonization or prior MRSA infection 1
• Systemic inflammatory response syndrome (fever >38°C, heart rate >90 bpm, respiratory rate >24 breaths/min) 1
• Failure to respond to beta-lactam therapy after 48-72 hours 1

Oral MRSA-Active Regimens (Choose One)

For purulent cellulitis with visible drainage:

• Clindamycin 300-450 mg orally every 6 hours for 5 days (monotherapy; covers both streptococci and MRSA if local resistance <10%) 1
• Trimethoprim-sulfamethoxazole 1-2 double-strength tablets twice daily PLUS cephalexin 500 mg four times daily for 5 days 1
• Doxycycline 100 mg orally twice daily PLUS cephalexin 500 mg four times daily for 5 days 1

Critical Pitfall to Avoid

Never use doxycycline or trimethoprim-sulfamethoxazole as monotherapy for typical cellulitis because they lack reliable activity against beta-hemolytic streptococci, which cause the vast majority of cases. 1 Some streptococcal strains possess intrinsic tetracycline resistance. 1

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Intravenous Treatment for Severe Disease

Indications for Hospitalization and IV Therapy

Hospitalize patients with any of the following: 1

• Systemic inflammatory response syndrome (fever, tachycardia, hypotension, altered mental status) 1
• Signs of necrotizing infection (severe pain out of proportion to examination, skin anesthesia, rapid progression, "wooden-hard" subcutaneous tissues, gas in tissue, bullous changes) 1
• Severe immunocompromise or neutropenia 1
• Failure of outpatient therapy after 24-48 hours 1

IV Antibiotic Regimens

For uncomplicated cellulitis requiring hospitalization (without MRSA risk factors):

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

For complicated cellulitis with MRSA risk factors:

• Vancomycin 15-20 mg/kg IV every 8-12 hours (target trough 15-20 mg/L; A-I evidence) 1
• Linezolid 600 mg IV twice daily (A-I evidence) 1
• Daptomycin 4 mg/kg IV once daily (A-I evidence) 1
• Clindamycin 600 mg IV three times daily (A-III evidence; only if local MRSA resistance <10%) 1

For severe cellulitis with systemic toxicity or suspected necrotizing fasciitis: Vancomycin 15-20 mg/kg IV every 8-12 hours PLUS piperacillin-tazobactam 3.375-4.5 g IV every 6 hours (or substitute a carbapenem or ceftriaxone plus metronidazole for the second agent). 1 This mandatory broad-spectrum combination therapy is required for patients with signs of systemic toxicity, rapid progression, or suspected necrotizing fasciitis. 1

Treatment Duration for Severe Infections

For complicated skin and soft tissue infections requiring hospitalization, treat for 7-14 days, individualized based on clinical response, with reassessment at 5 days. 1

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Essential Adjunctive Measures

Elevation of the affected extremity above heart level for at least 30 minutes three times daily hastens improvement by promoting gravity drainage of edema and inflammatory substances. 1

Examine interdigital toe spaces for tinea pedis, fissuring, scaling, or maceration; treating these conditions eradicates colonization and reduces recurrent infection risk. 1

Address predisposing conditions including venous insufficiency, lymphedema, chronic edema, obesity, and eczema to reduce recurrence. 1

Systemic corticosteroids (prednisone 40 mg daily for 7 days) could be considered in non-diabetic adults, though evidence is limited (weak recommendation, moderate evidence). 1 However, diabetes constitutes an absolute contraindication to adjunctive steroid therapy. 1

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Common Pitfalls to Avoid

Do not reflexively add MRSA coverage to all cellulitis cases; MRSA is uncommon in typical non-purulent cellulitis even in hospitals with high MRSA prevalence. 1 Adding MRSA coverage to beta-lactam therapy provides no additional benefit in typical cases. 1

Do not automatically extend therapy to 7-10 days based on residual erythema alone; some inflammation persists even after bacterial eradication. 1 Extending treatment to 10-14 days based on tradition rather than evidence increases antibiotic resistance without improving outcomes. 1

Do not delay surgical consultation if any signs of necrotizing infection are present; these infections progress rapidly and require emergent debridement. 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