What is the first-line therapy for uncomplicated cellulitis in an otherwise healthy adult?

First-Line Therapy for Uncomplicated Cellulitis

For uncomplicated cellulitis in an otherwise healthy adult, prescribe cephalexin 500 mg orally every 6 hours or dicloxacillin 250–500 mg orally every 6 hours for exactly 5 days if clinical improvement occurs. 1

Why Beta-Lactam Monotherapy Is Standard of Care

Beta-lactam monotherapy achieves 96% clinical success in typical non-purulent cellulitis because the causative organisms are overwhelmingly beta-hemolytic streptococci (especially Streptococcus pyogenes) and methicillin-sensitive Staphylococcus aureus (MSSA). 1, 2 A prospective study of 179 patients with diffuse, non-culturable cellulitis demonstrated that 73% of cases were caused by beta-hemolytic streptococci, and beta-lactam antibiotics achieved a 95.8% overall response rate. 2

MRSA is an uncommon cause of typical cellulitis even in high-prevalence settings, making routine MRSA coverage unnecessary and representing overtreatment that drives resistance. 1, 3

Recommended Oral Regimens

• Cephalexin 500 mg orally every 6 hours 1
• Dicloxacillin 250–500 mg orally every 6 hours 1
• Amoxicillin (dose not specified but listed as appropriate) 1
• Penicillin V 250–500 mg orally four times daily 1

All regimens should be given for 5 days if warmth, tenderness, and erythema are improving; 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 (and When NOT To)

Do NOT add MRSA coverage for typical non-purulent cellulitis without specific risk factors. 1, 3 Add MRSA-active antibiotics only when any of the following are present:

• Purulent drainage or exudate at the infection site 1
• Penetrating trauma or injection drug use 1, 4
• 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

MRSA-Active Regimens When Indicated

• Clindamycin 300–450 mg orally every 6 hours provides single-agent coverage for both streptococci and MRSA, but use only if local MRSA clindamycin resistance is <10%. 1
• Trimethoprim-sulfamethoxazole (TMP-SMX) 1–2 double-strength tablets twice daily PLUS a beta-lactam (cephalexin or amoxicillin) ensures streptococcal coverage, as TMP-SMX lacks reliable activity against beta-hemolytic streptococci. 1
• Doxycycline 100 mg orally twice daily PLUS a beta-lactam is appropriate for patients ≥8 years old; doxycycline is contraindicated in children <8 years and pregnant women. 1

In a retrospective cohort study from a high MRSA-prevalence area, antibiotics without community-associated MRSA activity had 4.22 times higher odds of treatment failure (95% CI 2.25–7.92). 5 However, this applies only to settings with documented high MRSA prevalence and specific risk factors—not to typical cellulitis. 1

Hospitalization Criteria

Admit 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 exam, skin anesthesia, rapid progression, "wooden-hard" tissue, gas in tissue, bullous changes) 1
• Severe immunocompromise or neutropenia 1
• Failure of outpatient treatment after 24–48 hours 1

For hospitalized patients requiring IV therapy, use cefazolin 1–2 g IV every 8 hours or nafcillin 2 g IV every 6 hours. 1 For severe cellulitis with systemic toxicity, use vancomycin 15–20 mg/kg IV every 8–12 hours PLUS piperacillin-tazobactam 3.375–4.5 g IV every 6 hours. 1

Essential Adjunctive Measures

• Elevate the affected extremity above heart level for at least 30 minutes three times daily to promote gravity drainage of edema. 1
• Examine interdigital toe spaces for tinea pedis, fissuring, scaling, or maceration; treat if present to reduce recurrence risk. 1
• Address predisposing conditions including venous insufficiency, lymphedema, chronic edema, obesity, and eczema. 1

Common Pitfalls to Avoid

• Do not reflexively add MRSA coverage to all cellulitis cases; MRSA is uncommon in typical non-purulent cellulitis even in high-prevalence settings. 1, 3
• Do not use doxycycline or TMP-SMX as monotherapy for typical cellulitis; they lack reliable activity against beta-hemolytic streptococci. 1
• Do not automatically extend treatment to 7–10 days based on residual erythema alone; inflammation may persist for days to weeks after bacterial eradication. 1
• Do not obtain blood cultures for typical uncomplicated cellulitis; they are positive in only ~5% of cases. 1

Reassessment and Treatment Failure

Reassess within 24–48 hours to verify clinical response; treatment failure rates of 21% have been reported with some oral regimens. 1 If no improvement after 48–72 hours of appropriate beta-lactam therapy, consider:

• Resistant organisms (add MRSA coverage) 1
• Abscess requiring drainage (obtain ultrasound if clinically uncertain) 1
• Cellulitis mimickers (deep vein thrombosis, venous stasis dermatitis, contact dermatitis) 3
• Necrotizing infection (obtain emergent surgical consultation) 1