What is the first‑line oral antibiotic regimen for non‑purulent cellulitis in an otherwise healthy adult without recent MRSA exposure, including alternatives for penicillin allergy or MRSA risk, and when should hospital admission be considered?

First-Line Oral Antibiotic Regimen for Non-Purulent Cellulitis

For an otherwise healthy adult with non-purulent cellulitis and no recent MRSA exposure, beta-lactam monotherapy with cephalexin 500 mg orally four times daily for 5 days is the standard of care, achieving 96% clinical success without requiring MRSA coverage. 1

Standard First-Line Treatment

Beta-lactam monotherapy is the definitive treatment for typical non-purulent cellulitis, targeting the primary pathogens: beta-hemolytic streptococci (especially Streptococcus pyogenes) and methicillin-sensitive Staphylococcus aureus. 1, 2, 3

Recommended Oral Beta-Lactam Options:

• Cephalexin 500 mg orally every 6 hours (most commonly prescribed) 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

Treatment duration is exactly 5 days if clinical improvement occurs; extend only if warmth, tenderness, or erythema have not improved within this timeframe. 1 This represents high-quality randomized controlled trial evidence that refutes the need for traditional 7-14 day courses. 1

When to Add MRSA Coverage

MRSA coverage should NOT be added routinely for typical non-purulent cellulitis, as MRSA is an uncommon cause even in high-prevalence settings. 1, 3, 4 However, add MRSA-active antibiotics ONLY when specific risk factors are present: 1, 5, 2

• Penetrating trauma or injection drug use 1, 5
• Purulent drainage or exudate visible 1, 5
• Known MRSA colonization or prior MRSA infection 1, 5, 2
• Systemic inflammatory response syndrome (SIRS): fever >38°C, tachycardia >90 bpm, tachypnea >24 rpm 1
• Failure to respond to beta-lactam therapy after 48-72 hours 1, 5

MRSA-Active Oral Regimens (when indicated):

• 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 rates are <10% 1, 5
• Trimethoprim-sulfamethoxazole (TMP-SMX) 1-2 double-strength tablets twice daily PLUS a beta-lactam (cephalexin or amoxicillin) 1, 5
• Doxycycline 100 mg orally twice daily PLUS a beta-lactam 1, 5

Critical pitfall: Never use doxycycline or TMP-SMX as monotherapy for typical cellulitis, as they lack reliable activity against beta-hemolytic streptococci, which cause the vast majority of non-purulent cellulitis cases. 1, 5

Alternatives for Penicillin Allergy

For patients with penicillin allergy (except immediate hypersensitivity reactions), cephalexin remains an option because cross-reactivity between penicillins and cephalosporins is only 2-4%. 1

For true penicillin allergy with immediate-type reactions:

• Clindamycin 300-450 mg orally every 6 hours (if local MRSA resistance <10%) 1
• Levofloxacin 500 mg orally once daily (reserve for beta-lactam allergies; lacks reliable MRSA coverage) 1
• Doxycycline 100 mg orally twice daily PLUS clindamycin (for dual streptococcal and MRSA coverage when beta-lactams cannot be used) 1

Hospital Admission Criteria

Hospitalize patients with any of the following high-risk features: 1, 5

• Systemic inflammatory response syndrome (SIRS) or sepsis 1
• Hypotension or hemodynamic instability 1
• Altered mental status or confusion 1
• Severe immunocompromise or neutropenia 1
• Rapidly progressive infection or concern for necrotizing fasciitis 1
• Failure of outpatient therapy 1
• Inability to tolerate oral medications 1

Inpatient IV Regimens:

• Cefazolin 1-2 g IV every 8 hours (preferred IV beta-lactam for uncomplicated cellulitis requiring hospitalization) 1
• Vancomycin 15-20 mg/kg IV every 8-12 hours (first-line for MRSA coverage; A-I evidence) 1, 5
• 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, 5

Essential Adjunctive Measures

Elevation of the affected extremity above heart level for at least 30 minutes three times daily hastens improvement by promoting gravity drainage of edema and inflammatory substances. 1

Treat predisposing conditions to reduce recurrence risk: 1

• Examine interdigital toe spaces for tinea pedis, fissuring, scaling, or maceration 1
• Address venous insufficiency and lymphedema 1
• Manage chronic edema 1

Common Pitfalls to Avoid

• Do not reflexively add MRSA coverage for typical non-purulent cellulitis without specific risk factors—this represents overtreatment and increases antibiotic resistance. 1, 4
• Do not extend treatment to 7-14 days based on residual erythema alone, as some inflammation persists even after bacterial eradication. 1
• Do not use beta-lactam antibiotics alone when MRSA is suspected or confirmed, as they have no activity against methicillin-resistant organisms. 5
• Reassess patients within 24-48 hours to verify clinical response, as treatment failure rates of 21% have been reported with some oral regimens. 1