What is the recommended empiric antibiotic regimen, dosing, and duration for cellulitis in an otherwise healthy adult without MRSA risk factors, including alternatives for penicillin allergy and guidance for severe or MRSA‑risk cases?

Cellulitis Treatment

First-Line Empiric Therapy for Uncomplicated Cellulitis

For otherwise healthy adults without MRSA risk factors, beta-lactam monotherapy is the standard of care and achieves 96% clinical success. 1

Recommended Oral Regimens (Choose One)

• Cephalexin 500 mg orally every 6 hours for 5 days 1
• Dicloxacillin 250-500 mg orally every 6 hours for 5 days 1
• Amoxicillin (standard dosing) for 5 days 1
• Penicillin V 250-500 mg orally four times daily for 5 days 1

Treatment duration is exactly 5 days if clinical improvement occurs; extend only if warmth, tenderness, or erythema have not improved within this timeframe. 1 Traditional 7-14 day courses are no longer necessary for uncomplicated cases. 1

Why Beta-Lactam Monotherapy Works

The majority of cellulitis cases (when organisms are identified) are caused by β-hemolytic streptococci and methicillin-sensitive Staphylococcus aureus. 2, 3 MRSA is an uncommon cause of typical nonpurulent cellulitis, even in hospitals with high MRSA prevalence. 1 Adding MRSA coverage to beta-lactam therapy provides no additional benefit in typical cases. 1

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Penicillin Allergy Alternatives

For patients with penicillin allergy (excluding immediate hypersensitivity), cephalexin remains appropriate because cross-reactivity is only 2-4%. 1

For true penicillin allergy with immediate hypersensitivity (urticaria, angioedema, bronchospasm, anaphylaxis), use clindamycin 300-450 mg orally every 6 hours for 5 days. 1 Clindamycin provides single-agent coverage for both streptococci and MRSA, eliminating the need for combination therapy. 1 However, use clindamycin only if local MRSA clindamycin resistance rates are <10%. 1, 4

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When to Add MRSA Coverage

MRSA-active antibiotics should be added ONLY when specific risk factors are present: 1, 4

• Penetrating trauma or injection drug use 1, 4
• Purulent drainage or exudate 1, 4
• Evidence of MRSA infection elsewhere or documented MRSA colonization 1, 4
• Systemic inflammatory response syndrome (SIRS): fever >38°C, tachycardia >90 bpm, tachypnea >24 rpm 1
• Failure to respond to beta-lactam therapy within 48-72 hours 1, 4

MRSA-Active Oral Regimens (When Risk Factors Present)

Option 1 (Preferred): Clindamycin 300-450 mg orally every 6 hours for 5 days—provides single-agent coverage for both streptococci and MRSA if local resistance <10%. 1, 4

Option 2: Combination therapy with trimethoprim-sulfamethoxazole (TMP-SMX) 1-2 double-strength tablets twice daily PLUS a beta-lactam (cephalexin 500 mg four times daily or dicloxacillin 500 mg four times daily) for 5 days. 1, 4 The beta-lactam is mandatory because TMP-SMX lacks reliable activity against β-hemolytic streptococci. 1, 4

Option 3: Doxycycline 100 mg orally twice daily PLUS a beta-lactam (cephalexin or dicloxacillin at standard doses) for 5 days. 1, 4 Never use doxycycline as monotherapy for typical cellulitis—it has unreliable activity against streptococci. 1, 4

Critical Pitfall to Avoid

Do not routinely add MRSA coverage for typical nonpurulent cellulitis without specific risk factors—this represents overtreatment and increases antibiotic resistance. 1 Even in areas with high community-acquired MRSA prevalence, beta-lactam monotherapy remains successful in 96% of typical cellulitis cases. 1

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Severe Cellulitis Requiring Hospitalization

Hospitalize patients with any of the following: 1

• Systemic inflammatory response syndrome (SIRS), fever, hypotension, or altered mental status 1
• Severe immunocompromise or neutropenia 1
• Signs of necrotizing fasciitis: severe pain out of proportion to examination, skin anesthesia, rapid progression, "wooden-hard" subcutaneous tissues, gas in tissue, or bullous changes 1

Inpatient IV Antibiotic Regimens

For uncomplicated cellulitis requiring hospitalization without MRSA risk factors:

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

For cellulitis with MRSA risk factors or purulent drainage:

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

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

• Vancomycin 15-20 mg/kg IV every 8-12 hours PLUS piperacillin-tazobactam 3.375-4.5 g IV every 6 hours 1, 4
• 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 cellulitis is 7-14 days, guided by clinical response, with reassessment at 5 days. 1

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Essential Adjunctive Measures

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

Treat predisposing conditions to reduce recurrence risk: 1

• Examine interdigital toe spaces for tinea pedis, fissuring, scaling, or maceration—treating these eradicates colonization and reduces recurrent infection 1
• Address venous insufficiency and lymphedema with compression stockings once acute infection resolves 1
• Manage chronic edema, obesity, and eczema 1

For patients with 3-4 episodes per year despite treating predisposing factors, consider prophylactic antibiotics: penicillin V 250 mg orally twice daily or erythromycin 250 mg twice daily. 1 Annual recurrence rates are 8-20% in patients with previous leg cellulitis. 1

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Special Considerations

Bite-Associated Cellulitis

For animal or human bite-associated cellulitis, use amoxicillin-clavulanate 875/125 mg orally twice daily for 5 days—it provides single-agent coverage for polymicrobial oral flora. 1

Diabetic Foot Cellulitis

Diabetic foot infections are polymicrobial and require broader coverage than typical cellulitis. 1 For mild diabetic foot infections, use amoxicillin-clavulanate, levofloxacin, or other agents with broader gram-negative and anaerobic coverage. 1 For moderate-to-severe diabetic foot infections, hospitalization and IV antibiotics (piperacillin-tazobactam, imipenem-cilastatin, or vancomycin plus ceftazidime) are required. 1

Reassessment and Treatment Failure

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

If cellulitis is spreading despite appropriate antibiotics, immediately evaluate for: 1

• Warning signs of necrotizing fasciitis (severe pain out of proportion, skin anesthesia, rapid progression, gas in tissue, systemic toxicity, bullous changes)—obtain emergent surgical consultation 1
• MRSA risk factors—switch to vancomycin or linezolid if MRSA is suspected 1
• Misdiagnosis—consider pseudocellulitis mimics such as venous stasis dermatitis, contact dermatitis, eczema, or lymphedema 3
• Abscess requiring drainage—obtain ultrasound if clinical uncertainty 1

Never continue ineffective antibiotics beyond 48 hours—progression despite appropriate therapy indicates resistant organisms or a deeper/different infection. 1