What is the first‑line oral β‑lactam for uncomplicated cellulitis in an adult without drug allergies or MRSA risk factors?

First-Line Drug for Uncomplicated Cellulitis

For uncomplicated cellulitis in an adult without drug allergies or MRSA risk factors, cephalexin 500 mg orally every 6 hours for 5 days is the first-line treatment. 1

Why Beta-Lactam Monotherapy Is Standard of Care

Beta-lactam monotherapy achieves 96% clinical success in typical cellulitis because the vast majority of cases are caused by beta-hemolytic streptococci (especially Streptococcus pyogenes) and methicillin-sensitive Staphylococcus aureus 1, 2. MRSA is an uncommon cause of typical nonpurulent cellulitis, even in areas with high community MRSA prevalence 1, 3.

Recommended First-Line Oral Beta-Lactams

Any of these agents provide appropriate coverage 1:

• Cephalexin 500 mg every 6 hours (most commonly prescribed)
• Dicloxacillin 250-500 mg every 6 hours
• Amoxicillin (standard dosing)
• Amoxicillin-clavulanate 875/125 mg twice daily
• Penicillin (appropriate for streptococcal coverage)

Cephalexin is typically preferred because it provides excellent coverage against both streptococci and methicillin-sensitive S. aureus, has convenient dosing, and is well-tolerated 1, 4.

Treatment Duration: 5 Days Is Sufficient

Treat for exactly 5 days if clinical improvement has occurred; extend only if symptoms have not improved within this timeframe 1. High-quality randomized controlled trial evidence demonstrates that 5-day courses are as effective as 10-day courses for uncomplicated cellulitis 1. Traditional 7-14 day courses are no longer necessary 1.

When MRSA Coverage Is NOT Needed

Do not routinely add MRSA coverage for typical cellulitis 1, 3. Adding MRSA-active agents to beta-lactam therapy provides no additional benefit in typical cases and promotes unnecessary antibiotic resistance 1. Even in settings with high community MRSA prevalence, combination therapy (cephalexin plus trimethoprim-sulfamethoxazole) is no more efficacious than cephalexin alone in pure cellulitis without abscess, ulcer, or purulent drainage 1, 5.

When to Add MRSA Coverage

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

• Purulent drainage or exudate (visible at the infection site)
• Penetrating trauma or injection drug use
• Known MRSA colonization or prior MRSA infection
• Systemic inflammatory response syndrome (fever >38°C, tachycardia >90 bpm, hypotension, altered mental status)
• Failure to respond to beta-lactam therapy after 48-72 hours

If these factors are present, use clindamycin 300-450 mg every 6 hours (covers both streptococci and MRSA as monotherapy, but only if local clindamycin resistance <10%) 1, or trimethoprim-sulfamethoxazole 1-2 double-strength tablets twice daily PLUS a beta-lactam 1.

Essential Adjunctive Measures

Beyond antibiotics, these interventions hasten improvement 1:

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

Critical Pitfalls to Avoid

• Do not extend treatment to 7-10 days automatically based on residual erythema alone; some inflammation persists even after bacterial eradication 1
• Do not add MRSA coverage reflexively simply because the patient is hospitalized or because MRSA is prevalent in your community 1
• Do not use doxycycline or trimethoprim-sulfamethoxazole as monotherapy for typical cellulitis; they lack reliable activity against beta-hemolytic streptococci 1
• Reassess within 24-48 hours to verify clinical response, as treatment failure rates of 21% have been reported with some oral regimens 1

When to Hospitalize

Admit patients with any of the following 1:

• Systemic inflammatory response syndrome (fever, tachycardia, hypotension, altered mental status)
• Severe immunocompromise or neutropenia
• Concern for deeper or necrotizing infection (severe pain out of proportion to exam, skin anesthesia, rapid progression, "wooden-hard" tissue)
• Failure of outpatient treatment after 24-48 hours

For hospitalized patients requiring IV therapy, cefazolin 1-2 g IV every 8 hours is the preferred IV beta-lactam 1.