What oral antibiotic should I prescribe for an adult with uncomplicated non‑purulent cellulitis without MRSA risk factors and no penicillin allergy?

Oral Antibiotic for Uncomplicated Non-Purulent Cellulitis

For an adult with uncomplicated non-purulent cellulitis without MRSA risk factors and no penicillin allergy, prescribe cephalexin 500 mg orally every 6 hours for 5 days. 1

First-Line Treatment

• Cephalexin is the preferred oral beta-lactam because it provides excellent coverage against beta-hemolytic streptococci (especially Streptococcus pyogenes) and methicillin-sensitive Staphylococcus aureus, which are the primary pathogens in typical cellulitis 1
• Beta-lactam monotherapy succeeds in 96% of uncomplicated cellulitis cases, confirming that MRSA coverage is unnecessary in this scenario 1
• Alternative oral beta-lactams include dicloxacillin 250-500 mg every 6 hours, amoxicillin, or penicillin V 250-500 mg four times daily 1

Treatment Duration

• Treat for exactly 5 days if clinical improvement occurs (reduced warmth, tenderness, and erythema) 1
• Extend treatment only if symptoms have not improved within this 5-day timeframe—do not reflexively extend to 7-10 days based on residual erythema alone, as some inflammation persists even after bacterial eradication 1
• Reassess at 48-72 hours to verify clinical response; treatment failure rates of 21% have been reported with some regimens 2

Why MRSA Coverage Is NOT Needed

• MRSA is an uncommon cause of typical non-purulent cellulitis, even in high-prevalence settings 1
• Adding trimethoprim-sulfamethoxazole to cephalexin provides no additional benefit in pure cellulitis without abscess, ulcer, or purulent drainage 1, 3, 4
• Two high-quality randomized controlled trials demonstrated that cephalexin plus trimethoprim-sulfamethoxazole was no more effective than cephalexin alone for uncomplicated cellulitis 3, 4

When to Add MRSA Coverage (Not Applicable Here)

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

• Penetrating trauma or injection drug use
• Purulent drainage or exudate
• Known MRSA colonization or infection elsewhere
• Systemic inflammatory response syndrome (SIRS)

For these scenarios, use clindamycin 300-450 mg orally every 6 hours (if local MRSA clindamycin resistance <10%), or combine trimethoprim-sulfamethoxazole 1-2 double-strength tablets twice daily plus a beta-lactam 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 hasten improvement 1
• Examine interdigital toe spaces for tinea pedis, fissuring, or maceration, and treat these to eradicate colonization and reduce recurrence 1
• Address predisposing conditions including venous insufficiency, lymphedema, and chronic edema 1

Common Pitfalls to Avoid

• Do not add MRSA coverage reflexively for typical non-purulent cellulitis—this represents overtreatment and increases antibiotic resistance without improving outcomes 1
• Do not use doxycycline or trimethoprim-sulfamethoxazole as monotherapy for typical cellulitis, as their activity against beta-hemolytic streptococci is unreliable 1
• Do not extend treatment to 10-14 days based on tradition rather than evidence—this increases resistance without improving outcomes in uncomplicated cases 1

When to Hospitalize

Admit for IV antibiotics if any of the following are present 1:

• Systemic inflammatory response syndrome (fever >38°C, tachycardia >90 bpm, tachypnea >24 rpm)
• Hypotension or altered mental status
• Severe immunocompromise or neutropenia
• Signs of necrotizing fasciitis (severe pain out of proportion to exam, skin anesthesia, rapid progression, "wooden-hard" tissues)