What is the most appropriate empiric antibiotic for uncomplicated non‑purulent cellulitis in an otherwise healthy adult?

Best Antibiotic for Uncomplicated Non-Purulent Cellulitis

For an otherwise healthy adult with uncomplicated non-purulent cellulitis, beta-lactam monotherapy—specifically cephalexin 500 mg orally four times daily for 5 days—is the standard of care, with a 96% success rate. 1

First-Line Treatment Algorithm

Standard Beta-Lactam Monotherapy

• Cephalexin 500 mg orally every 6 hours (four times daily) is the preferred oral beta-lactam for typical non-purulent cellulitis, providing excellent coverage against beta-hemolytic streptococci (especially Streptococcus pyogenes) and methicillin-sensitive Staphylococcus aureus. 1
• Alternative oral beta-lactams include dicloxacillin 250-500 mg every 6 hours, amoxicillin, or penicillin V 250-500 mg four times daily. 1
• MRSA coverage is NOT routinely necessary for typical non-purulent cellulitis, as MRSA is an uncommon cause even in high-prevalence settings. 1

Treatment Duration

• Treat for exactly 5 days if clinical improvement occurs—defined as resolution of warmth and tenderness, improving erythema, and absence of fever. 1
• Extend treatment beyond 5 days only if symptoms have not improved within this timeframe. 1
• Traditional 7-14 day courses are no longer necessary for uncomplicated cases, as 5-day courses are equally effective. 1

When to Add MRSA Coverage (Combination Therapy)

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

• Penetrating trauma or injection drug use 1
• Purulent drainage or exudate (even without drainable abscess) 1
• Known MRSA colonization or evidence of MRSA infection elsewhere 1
• Systemic inflammatory response syndrome (SIRS) with fever, tachycardia, or hypotension 1

Recommended MRSA-Active Regimens

• Clindamycin 300-450 mg orally every 6 hours provides single-agent coverage for both streptococci and MRSA, eliminating the need for combination therapy—but use only if local MRSA clindamycin resistance rates are <10%. 1
• Alternative combination regimens include trimethoprim-sulfamethoxazole (1-2 double-strength tablets twice daily) PLUS a beta-lactam (cephalexin or amoxicillin). 1
• Doxycycline 100 mg orally twice daily PLUS a beta-lactam is another option. 1

Critical Evidence Supporting Beta-Lactam Monotherapy

The highest quality evidence demonstrates that adding MRSA coverage provides no benefit in typical cellulitis:

• A 2017 multicenter randomized controlled trial (n=500) showed that cephalexin plus trimethoprim-sulfamethoxazole yielded an 83.5% cure rate versus 85.5% for cephalexin alone—a non-significant difference of -2.0% (95% CI, -9.7% to 5.7%; P=0.50). 2
• A 2013 randomized controlled trial (n=153) confirmed that adding trimethoprim-sulfamethoxazole to cephalexin did not improve outcomes: 85% cure rate versus 82% for cephalexin alone (risk difference 2.7%, 95% CI -9.3% to 15%; P=0.66). 3
• Beta-lactam therapy achieves 96% success rates in typical non-purulent cellulitis, confirming that MRSA coverage is usually unnecessary. 1

Common Pitfalls to Avoid

• Do not reflexively add MRSA coverage simply because the patient is hospitalized or because MRSA prevalence is high in your community—typical non-purulent cellulitis remains predominantly streptococcal. 1
• Do not use doxycycline or trimethoprim-sulfamethoxazole as monotherapy for typical cellulitis, as their activity against beta-hemolytic streptococci is unreliable. 1, 4
• Do not extend treatment to 10-14 days based on residual erythema alone—some inflammation persists even after bacterial eradication. 1
• Do not continue ineffective antibiotics beyond 48 hours—progression despite appropriate therapy indicates either resistant organisms or a deeper/different infection than initially recognized. 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 and inflammatory substances. 1
• Examine interdigital toe spaces for tinea pedis, fissuring, scaling, or maceration—treating these eradicates colonization and reduces recurrent infection. 1
• Address predisposing conditions including venous insufficiency, lymphedema, and chronic edema. 1

When to Hospitalize or Escalate Therapy

Hospitalize if any of the following are present: 1

• Systemic inflammatory response syndrome (SIRS): fever >38°C, tachycardia >90 bpm, tachypnea >24 rpm 1
• Hypotension or hemodynamic instability 1
• Altered mental status or confusion 1
• Severe immunocompromise or neutropenia 1
• Concern for necrotizing fasciitis (severe pain out of proportion to exam, skin anesthesia, rapid progression, "wooden-hard" subcutaneous tissues, gas in tissue) 1

For severe cellulitis with systemic toxicity or suspected necrotizing fasciitis, use 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. 5, 1