In an adult with uncomplicated cellulitis, no penicillin allergy, and low MRSA risk, is amoxicillin an appropriate first‑line oral therapy?

Amoxicillin for Uncomplicated Cellulitis

Amoxicillin is an appropriate and effective first-line oral antibiotic for uncomplicated cellulitis in adults without penicillin allergy and low MRSA risk. 1, 2

Why Amoxicillin Works for Typical Cellulitis

Beta-lactam monotherapy—including amoxicillin—achieves 96% clinical success in typical nonpurulent cellulitis because the primary pathogens are beta-hemolytic streptococci (especially Streptococcus pyogenes) and methicillin-sensitive Staphylococcus aureus (MSSA). 1, 3 MRSA is an uncommon cause of typical cellulitis even in high-prevalence settings, making routine MRSA coverage unnecessary. 1, 4

The Infectious Diseases Society of America explicitly lists amoxicillin alongside penicillin, cephalexin, dicloxacillin, and clindamycin as recommended oral agents for uncomplicated cellulitis. 1

Dosing and Duration

• Amoxicillin 500 mg orally three times daily for 5 days is the standard regimen. 1
• Extend treatment only if warmth, tenderness, or erythema have not improved after 5 days—do not reflexively extend to 7–10 days based on residual redness alone. 1, 2
• High-quality randomized controlled trial evidence confirms that 5-day courses are as effective as 10-day courses for uncomplicated cellulitis. 2

When Amoxicillin Is Appropriate

Use amoxicillin for nonpurulent cellulitis (no drainage, exudate, or abscess) in patients who:

• Have no penetrating trauma or injection drug use 1
• Show no purulent drainage or exudate 1
• Lack known MRSA colonization or prior MRSA infection 1
• Do not have systemic inflammatory response syndrome (fever >38°C, tachycardia, hypotension) 1
• Are not immunocompromised 1

When to Add MRSA Coverage (and Skip Amoxicillin Monotherapy)

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

• Purulent drainage or exudate at the infection site 1, 2
• Penetrating trauma or injection drug use 1, 2
• Known MRSA colonization or prior MRSA infection 1
• Systemic inflammatory response syndrome (fever, tachycardia, hypotension, altered mental status) 1
• Failure to respond to beta-lactam therapy after 48–72 hours 1

In these scenarios, switch to clindamycin 300–450 mg orally every 6 hours (if local MRSA clindamycin resistance <10%) or use trimethoprim-sulfamethoxazole 1–2 double-strength tablets twice daily PLUS a beta-lactam (because TMP-SMX lacks reliable streptococcal coverage). 1

Alternative Beta-Lactams

If amoxicillin is unavailable or not preferred:

• Cephalexin 500 mg orally every 6 hours 1, 2
• Dicloxacillin 250–500 mg orally every 6 hours 1, 2
• Penicillin V 250–500 mg orally four times daily 1

All provide equivalent streptococcal and MSSA coverage. 1

Critical Pitfalls to Avoid

• Do not routinely add MRSA coverage for typical nonpurulent cellulitis without the specified risk factors—this represents overtreatment and drives antibiotic resistance. 1
• Do not use doxycycline or trimethoprim-sulfamethoxazole as monotherapy for typical cellulitis; they lack reliable activity against beta-hemolytic streptococci. 1
• Do not extend treatment to 7–10 days based on tradition—extend only if warmth, tenderness, or erythema persist after 5 days. 1, 2
• Do not confuse cellulitis with purulent collections (abscesses, furuncles)—the latter require incision and drainage as primary treatment, not antibiotics alone. 1

Adjunctive Measures to Accelerate Recovery

• 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, 2
• Examine interdigital toe spaces for tinea pedis, fissuring, or maceration and treat if present—this eradicates colonization and reduces recurrence risk. 1, 2
• Address predisposing conditions such as venous insufficiency, lymphedema, chronic edema, and eczema. 1, 2

When to Hospitalize

Admit patients with:

• 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) 1
• Severe immunocompromise or neutropenia 1
• Failure of outpatient treatment after 24–48 hours 1

For hospitalized patients, use cefazolin 1–2 g IV every 8 hours or vancomycin 15–20 mg/kg IV every 8–12 hours if MRSA coverage is needed. 1

Evidence Quality

The recommendation for beta-lactam monotherapy (including amoxicillin) is supported by A-I level evidence from the Infectious Diseases Society of America guidelines, representing strong recommendations based on high-quality data. 1 The 5-day treatment duration is supported by high-quality randomized controlled trials showing no difference in outcomes compared with 10-day courses. 2