What is the recommended antibiotic regimen for inpatient management of simple cellulitis?

Inpatient Management of Simple Cellulitis

For simple, uncomplicated cellulitis requiring hospitalization, IV cefazolin 1-2 g every 8 hours is the preferred first-line antibiotic, treating for 5 days if clinical improvement occurs, with extension only if symptoms have not improved within this timeframe. 1

Initial Assessment and Risk Stratification

Upon admission, assess for signs of systemic toxicity including fever, hypotension, tachycardia, confusion, or altered mental status 1. Obtain blood cultures specifically in patients with malignancy, severe systemic features, neutropenia, or severe immunodeficiency 1.

Critical distinction: Determine if this is truly simple cellulitis (nonpurulent, no MRSA risk factors) versus complicated infection requiring broader coverage 1. Simple cellulitis presents with erythema, warmth, and tenderness without purulent drainage or exudate 1.

First-Line Antibiotic Selection

Standard IV Beta-Lactam Monotherapy

• Cefazolin 1-2 g IV every 8 hours is the preferred agent for hospitalized patients with uncomplicated cellulitis 1, 2
• Alternative: Oxacillin 2 g IV every 6 hours 1
• Alternative: Nafcillin 2 g IV every 6 hours 1

Key evidence: Beta-lactam monotherapy succeeds in 96% of typical cellulitis cases, confirming MRSA coverage is usually unnecessary even in the inpatient setting 1. MRSA is an uncommon cause of typical cellulitis, even in hospitals with high MRSA prevalence 1.

Common Pitfall to Avoid

Do not reflexively add MRSA coverage simply because the patient is hospitalized 1. The decision to add MRSA-active therapy should be based on specific risk factors, not admission status alone 1.

When to Add MRSA Coverage

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

• Purulent drainage or exudate 1
• Penetrating trauma or injection drug use 1
• Evidence of MRSA infection elsewhere or known nasal colonization 1
• Failure to respond to beta-lactam therapy within 24-48 hours 1

MRSA-Active IV Regimens

If MRSA coverage is indicated:

• 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 three times daily (only if local MRSA resistance <10%, A-III evidence) 1

Treatment Duration

Standard duration is 5 days if clinical improvement occurs 1, 3, 4. Extend treatment beyond 5 days ONLY if the infection has not improved within this timeframe 1.

High-quality evidence: A randomized, double-blind trial demonstrated that 5 days of antibiotic therapy achieved clinical resolution in 98% of patients with uncomplicated cellulitis, equivalent to 10-day courses 3. Recovery is not associated with treatment duration beyond 5 days 4.

Factors Associated with Longer Treatment Duration

While 5 days is standard, certain factors may necessitate extension 5:

• Advanced patient age 5
• Elevated C-reactive protein levels before treatment 5
• Coexisting diabetes mellitus 5
• Concurrent bloodstream infection 5

However, these factors should not automatically trigger longer courses—reassess at day 5 and extend only if clinical improvement has not occurred 1.

Transition to Oral Therapy

Transition to oral antibiotics once clinical improvement is demonstrated, typically after a minimum of 4 days of IV treatment 1:

• Cephalexin 500 mg orally every 6 hours 1
• Dicloxacillin 250-500 mg orally every 6 hours 1
• Clindamycin 300-450 mg orally every 6 hours (if MRSA coverage needed and local resistance <10%) 1

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

Severe Cellulitis Requiring Broad-Spectrum Coverage

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 1
• Alternative: Linezolid 600 mg IV twice daily PLUS piperacillin-tazobactam 1
• Alternative: Vancomycin PLUS a carbapenem 1
• Alternative: Vancomycin PLUS ceftriaxone 2 g IV daily and metronidazole 500 mg IV every 8 hours 1

For severe infections, treatment duration is 7-14 days, guided by clinical response 1.

Essential Adjunctive Measures

Elevation and Drainage

Elevate the affected extremity above heart level for at least 30 minutes three times daily 1. This promotes gravity drainage of edema and inflammatory substances, hastening clinical improvement 1.

Address Predisposing Conditions

• Examine interdigital toe spaces for tinea pedis, fissuring, scaling, or maceration 1
• Treat toe web abnormalities to eradicate colonization and reduce recurrent infection 1
• Address venous insufficiency, lymphedema, and chronic edema 1

Consider Corticosteroids

Systemic corticosteroids (prednisone 40 mg daily for 7 days) could be considered in non-diabetic adults, though evidence is limited 1.

Reassessment and Treatment Failure

Mandatory reassessment within 24-48 hours is essential to verify clinical response 1. Treatment failure rates of 21% have been reported with some regimens, particularly in patients with chronic venous disease 6.

Warning Signs Requiring Surgical Consultation

Immediately obtain surgical consultation if any of the following are present 1:

• Severe pain out of proportion to examination findings 1
• Skin anesthesia 1
• Rapid progression despite appropriate therapy 1
• "Wooden-hard" subcutaneous tissues suggesting necrotizing infection 1
• Gas in tissue 1
• Bullous changes 1

Do not delay surgical consultation if any signs of necrotizing infection are present, as these infections progress rapidly and require debridement 1.