Treatment of Uncomplicated Cellulitis
For uncomplicated cellulitis, treat with beta-lactam monotherapy (cephalexin 500 mg every 6 hours or dicloxacillin 250-500 mg every 6 hours) for 5 days if clinical improvement occurs—MRSA coverage is unnecessary in typical cases and provides no additional benefit. 1
First-Line Antibiotic Selection
Oral beta-lactam monotherapy is the standard of care, with a 96% success rate confirming that MRSA coverage is routinely unnecessary 1. The recommended oral agents include:
- Cephalexin 500 mg every 6 hours (preferred first-line agent) 1
- Dicloxacillin 250-500 mg every 6 hours 1
- Amoxicillin 1
- Amoxicillin-clavulanate 875/125 mg twice daily (reasonable for bite-associated cellulitis) 1
- Clindamycin 300-450 mg three times daily (covers both streptococci and MRSA if local resistance <10%) 1
For patients requiring parenteral therapy due to inability to tolerate oral medications or severe illness, use cefazolin 1-2 g IV every 8 hours or nafcillin 2, 1. For life-threatening penicillin allergies, use clindamycin or vancomycin 2.
Treatment Duration
Treat for exactly 5 days if clinical improvement has occurred; extend only if symptoms have not improved within this timeframe 1, 3. A randomized controlled trial demonstrated that 5 days of levofloxacin therapy achieved clinical cure in 98% of patients, identical to 10-day therapy 3. Traditional 7-14 day courses are no longer necessary for uncomplicated cases 1.
When MRSA Coverage is NOT Needed
Do not add MRSA coverage for typical nonpurulent cellulitis—this is the most common pitfall 1. Beta-lactam treatment succeeds in 96% of patients, and combination therapy with trimethoprim-sulfamethoxazole plus cephalexin provides no additional benefit over cephalexin alone in pure cellulitis without abscess, ulcer, or purulent drainage 1, 4. Even in settings with high community MRSA prevalence, MRSA remains an uncommon cause of typical cellulitis 1, 5.
When to Add MRSA Coverage
Add MRSA-active antibiotics only when these specific risk factors are present 1:
- Penetrating trauma or injection drug use 1
- Purulent drainage or exudate 1
- Evidence of MRSA infection elsewhere or known nasal MRSA colonization 1
- Systemic inflammatory response syndrome (SIRS) with fever, hypotension, tachycardia, or altered mental status 1
When MRSA coverage is indicated, use:
- Trimethoprim-sulfamethoxazole (320 mg/1600 mg twice daily) PLUS a beta-lactam 1
- Doxycycline (100 mg twice daily) PLUS a beta-lactam 1
- Clindamycin monotherapy (provides coverage for both streptococci and MRSA, avoiding need for combination therapy) 1
Critical caveat: Never use doxycycline or trimethoprim-sulfamethoxazole as monotherapy for typical nonpurulent cellulitis, as tetracyclines and sulfonamides lack reliable activity against beta-hemolytic streptococci 1.
Severe Infections Requiring Hospitalization
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 and metronidazole 1
For documented group A streptococcal necrotizing fasciitis specifically, use penicillin plus clindamycin 1.
Essential Adjunctive Measures
Beyond antibiotics, these interventions hasten recovery 2, 1:
- Elevate the affected extremity to promote gravity drainage of edema and inflammatory substances 2, 1
- Treat predisposing conditions: tinea pedis, venous eczema, trauma, lymphedema, venous insufficiency, obesity 2, 1
- Examine interdigital toe spaces for maceration, fissuring, or fungal infection 1
- Consider systemic corticosteroids (prednisone 40 mg daily for 7 days) in non-diabetic adults—one randomized trial showed shortened healing time by 1 day, though evidence is limited 2, 1
Monitoring and Treatment Failure
Reassess within 24-48 hours to verify clinical response 1. Failure to improve with appropriate first-line antibiotics should prompt consideration for 5, 6:
- Resistant organisms (though rare with proper initial selection)
- Cellulitis mimickers: venous stasis dermatitis, contact dermatitis, eczema, lymphedema, erythema migrans 6
- Deeper infection or necrotizing fasciitis: severe pain out of proportion to examination, skin anesthesia, rapid progression, gas in tissue, bullous changes 1
- Underlying complications: diabetes, chronic liver disease, chronic kidney disease, immunosuppression 5
Blood cultures are positive in only 5% of cases and are unnecessary for typical cellulitis 1. Obtain blood cultures only in patients with severe systemic features, malignancy, neutropenia, or unusual predisposing factors 1.
Recurrence Prevention
For patients with frequent recurrences despite treating predisposing factors, consider prophylactic antibiotics 2: