What is the recommended management of cellulitis in an otherwise healthy adult, including first‑line oral antibiotics, adjustments for MRSA risk or beta‑lactam allergy, and criteria for intravenous therapy or hospital admission?

Management of Cellulitis in Otherwise Healthy Adults

First-Line Oral Antibiotic Therapy

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 include:

• Cephalexin 500 mg every 6 hours 1
• Dicloxacillin 250-500 mg every 6 hours 1
• Amoxicillin 500 mg three times daily 1
• Penicillin V 250-500 mg four times daily 1

Treatment duration is exactly 5 days if clinical improvement occurs (reduced warmth, tenderness, improving erythema, no fever); extend only if 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

When to Add MRSA Coverage

Do NOT routinely add MRSA coverage for typical nonpurulent cellulitis. MRSA coverage should be added ONLY when specific risk factors are present: 1

• 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) – 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

MRSA-Active Oral Regimens (when indicated)

For purulent cellulitis requiring MRSA coverage, choose ONE of the following:

• Clindamycin 300-450 mg every 6 hours as monotherapy – provides single-agent coverage for both streptococci and MRSA, but use ONLY if local MRSA clindamycin resistance is <10% 1, 2

• Trimethoprim-sulfamethoxazole (TMP-SMX) 1-2 double-strength tablets twice daily PLUS a beta-lactam (cephalexin or amoxicillin) – combination therapy is mandatory because TMP-SMX lacks reliable streptococcal coverage 1, 2

• Doxycycline 100 mg twice daily PLUS a beta-lactam – combination therapy is mandatory because doxycycline lacks reliable activity against beta-hemolytic streptococci 1, 2

Critical pitfall: Never use doxycycline or TMP-SMX as monotherapy for typical cellulitis, as they miss streptococcal pathogens in ~96% of cases. 1

Management of Beta-Lactam Allergy

For non-immediate penicillin allergy (e.g., maculopapular rash):

• Cephalosporins remain acceptable because cross-reactivity is only 2-4%, primarily based on R1 side chain similarity 1
• Avoid cephalexin in patients with confirmed immediate-type amoxicillin allergy due to identical R1 side chains 1

For true penicillin allergy or immediate hypersensitivity:

• Clindamycin 300-450 mg every 6 hours – provides single-agent coverage for both streptococci and MRSA if local resistance <10% 1
• Levofloxacin 500 mg daily – reserve for patients with beta-lactam allergies; lacks adequate MRSA coverage 1

Criteria for Intravenous Therapy and Hospital Admission

Hospitalize patients with ANY of the following:

• 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
• Age <6 months with moderate-to-severe disease (pediatric) 1

Intravenous Antibiotic Regimens

For uncomplicated cellulitis requiring hospitalization (no MRSA risk factors):

• Cefazolin 1-2 g IV every 8 hours (preferred) 1
• Nafcillin or 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 (first-line, A-I evidence) 1, 2
• Linezolid 600 mg IV twice daily (alternative, A-I evidence) 1
• Daptomycin 4 mg/kg IV once daily (alternative, A-I evidence) 1
• Clindamycin 600 mg IV every 8 hours (alternative, A-III evidence, only if local 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 1, 2
• Alternative combinations: vancomycin plus a carbapenem (meropenem 1 g IV every 8 hours) OR vancomycin plus ceftriaxone 2 g IV daily and metronidazole 500 mg IV every 8 hours 1

Treatment duration for complicated infections is 7-14 days, individualized based on clinical response. 1

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

Treat predisposing conditions:

• Examine interdigital toe spaces for tinea pedis, fissuring, scaling, or maceration and treat if present 1
• Address venous insufficiency, lymphedema, and chronic edema 1
• Manage obesity, eczema, and other skin breakdown 1

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

Critical Reassessment Points

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

If no improvement after 48-72 hours of appropriate therapy, consider:

• Resistant organisms (MRSA) 1
• Undrained abscess – obtain ultrasound if clinical uncertainty exists 1
• Deeper infection (necrotizing fasciitis, osteomyelitis) 1
• Alternative diagnoses 1

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