What is the recommended outpatient antibiotic regimen for an otherwise healthy adult with uncomplicated non‑purulent cellulitis, including options for β‑lactam allergy and for patients with community‑acquired MRSA risk?

Outpatient Treatment of Uncomplicated Cellulitis

For otherwise healthy adults with uncomplicated non-purulent cellulitis, prescribe a beta-lactam antibiotic such as cephalexin 500 mg orally every 6 hours or dicloxacillin 250–500 mg orally every 6 hours for exactly 5 days, extending only if warmth, tenderness, or erythema have not improved. 1

First-Line Beta-Lactam Monotherapy

Beta-lactam antibiotics achieve approximately 96% clinical success in typical non-purulent cellulitis because the primary pathogens are beta-hemolytic streptococci (especially Streptococcus pyogenes) and methicillin-sensitive Staphylococcus aureus. 1, 2 MRSA is an uncommon cause of typical cellulitis even in high-prevalence settings, making routine MRSA coverage unnecessary and potentially harmful through increased resistance. 1, 3

Recommended oral beta-lactam options:

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

All regimens should be prescribed for 5 days if clinical improvement occurs (resolution of warmth/tenderness, improving erythema, absence of fever); extend only if symptoms persist. 1 High-quality randomized controlled trial evidence demonstrates that 5-day courses are as effective as 10-day courses, with 98% clinical resolution at 14 days and no relapses by 28 days. 1

When to Add MRSA Coverage

Add MRSA-active antibiotics only when specific risk factors are present: 1, 3

• Penetrating trauma or injection drug use 1
• Visible purulent drainage or exudate 1
• 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

In the absence of these factors, adding MRSA coverage provides no outcome benefit and promotes antimicrobial resistance. 1, 4

MRSA-Active Regimens (When Indicated)

For purulent cellulitis with visible drainage:

• 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, 5

For non-purulent cellulitis requiring MRSA coverage (combination therapy mandatory):

• Trimethoprim-sulfamethoxazole 1–2 double-strength tablets twice daily PLUS cephalexin 500 mg every 6 hours 1, 5
• Doxycycline 100 mg twice daily PLUS cephalexin 500 mg every 6 hours 1, 5

Never use doxycycline or trimethoprim-sulfamethoxazole as monotherapy for typical cellulitis—they lack reliable activity against beta-hemolytic streptococci, which cause the vast majority of cases. 1, 5

Management of Beta-Lactam Allergy

For non-immediate penicillin allergy (e.g., maculopapular rash):

• Cephalexin remains acceptable because cross-reactivity is only 2–4%; avoid only in confirmed immediate-type amoxicillin allergy due to identical R1 side chains 1

For true penicillin allergy:

• Clindamycin 300–450 mg orally every 6 hours (if local MRSA clindamycin resistance <10%) 1
• Levofloxacin 500 mg orally once daily (reserve for beta-lactam-allergic patients; lacks MRSA coverage) 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, which hastens clinical improvement. 1

Examine interdigital toe spaces for tinea pedis, fissuring, scaling, or maceration; treating these conditions eradicates colonization and reduces recurrent infection. 1

Address predisposing conditions including venous insufficiency, lymphedema, chronic edema, obesity, and eczema to minimize recurrence risk. 1, 3

Hospitalization Criteria

Admit patients when any of the following are present: 1

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

For hospitalized patients requiring IV therapy:

• Cefazolin 1–2 g IV every 8 hours (preferred IV beta-lactam for uncomplicated cellulitis) 1
• Vancomycin 15–20 mg/kg IV every 8–12 hours PLUS piperacillin-tazobactam 3.375–4.5 g IV every 6 hours (for severe cellulitis with systemic toxicity or suspected necrotizing infection) 1

Critical Pitfalls to Avoid

Do not add MRSA coverage reflexively for typical non-purulent cellulitis without the specified risk factors—this overtreats approximately 96% of cases and drives resistance. 1, 4

Do not automatically extend therapy to 7–10 days based solely on residual erythema; extend only if warmth, tenderness, or erythema have not improved after 5 days. 1

Do not delay surgical consultation when signs of necrotizing infection (disproportionate pain, rapid progression, bullae, gas, necrosis) are present—timely debridement is critical. 1

Reassess patients within 24–48 hours to confirm improvement; oral regimens have reported failure rates around 21% if no response is seen. 1