What is the first‑line empiric antibiotic regimen, including dose, route, and duration, for an otherwise healthy adult with uncomplicated non‑purulent cellulitis?

First-Line Empiric Antibiotic Regimen for Uncomplicated Non-Purulent Cellulitis

For an otherwise healthy adult with uncomplicated non-purulent cellulitis, prescribe cephalexin 500 mg orally every 6 hours (four times daily) for 5 days, extending only if warmth, tenderness, or erythema have not improved within this timeframe. 1

Why Beta-Lactam Monotherapy Is Standard of Care

• Beta-lactam monotherapy achieves a 96% clinical success rate in typical uncomplicated cellulitis, confirming that MRSA coverage is usually unnecessary in this population 1, 2
• Beta-hemolytic streptococci (especially Streptococcus pyogenes) and methicillin-sensitive Staphylococcus aureus cause the vast majority of non-purulent cellulitis, even in settings with high community MRSA prevalence 1, 3, 4, 2
• A landmark prospective study demonstrated that 73% of diffuse, nonculturable cellulitis cases are caused by beta-hemolytic streptococci, with a 97% response rate to beta-lactam antibiotics 2

Alternative First-Line Beta-Lactam Options

If cephalexin is unavailable or contraindicated, equally effective alternatives include:

• 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 provide excellent streptococcal and methicillin-sensitive S. aureus coverage 1

Treatment Duration: The 5-Day Evidence

• High-quality randomized controlled trial evidence demonstrates that 5-day courses are as effective as 10-day courses for uncomplicated cellulitis 1
• Extend treatment beyond 5 days ONLY if the infection has not improved—meaning persistent warmth, tenderness, or expanding erythema 1
• Traditional 7-14 day courses are no longer necessary and represent overtreatment 1

When MRSA Coverage Is NOT Needed

Do not add MRSA coverage for typical non-purulent cellulitis unless specific risk factors are present. 1, 5, 4 MRSA is an uncommon cause of diffuse cellulitis even in high-prevalence settings 1, 5

When to Add MRSA Coverage

Add MRSA-active antibiotics ONLY when one or more of these risk factors are present:

• Purulent drainage or exudate (visible pus) 1, 5
• Penetrating trauma or injection drug use 1, 5, 3
• Known MRSA colonization or prior MRSA infection 1, 5
• Systemic inflammatory response syndrome (SIRS): fever >38°C, tachycardia >90 bpm, tachypnea >24 rpm 1, 5
• Failure to respond to beta-lactam therapy after 48-72 hours 1, 5

MRSA-Active Regimens (When Risk Factors Present)

If MRSA coverage is required, use:

• Clindamycin 300-450 mg orally every 6 hours as monotherapy (covers both streptococci and MRSA), but ONLY if local MRSA clindamycin resistance rates are <10% 1, 5
• Trimethoprim-sulfamethoxazole (TMP-SMX) 1-2 double-strength tablets twice daily PLUS cephalexin 500 mg four times daily (combination therapy required because TMP-SMX lacks reliable streptococcal coverage) 1, 5
• Doxycycline 100 mg orally twice daily PLUS cephalexin 500 mg four times daily (combination therapy required because doxycycline lacks reliable streptococcal coverage) 1, 5

Critical Pitfalls to Avoid

• Never use doxycycline or TMP-SMX as monotherapy for typical cellulitis—these agents lack reliable activity against beta-hemolytic streptococci, which cause the majority of cases 1, 5
• Do not reflexively add MRSA coverage simply because community MRSA rates are high—the pathogen profile of diffuse cellulitis differs from purulent abscesses 1, 5, 2
• Do not extend antibiotics to 10-14 days based on residual erythema alone—some inflammation persists even after bacterial eradication 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 1
• Examine interdigital toe spaces for tinea pedis, fissuring, or maceration and treat these conditions to eradicate colonization and reduce recurrence 1
• Address predisposing conditions including venous insufficiency, lymphedema, and chronic edema 1

When to Hospitalize

Admit patients with any of the following:

• Systemic inflammatory response syndrome (SIRS), hypotension, or altered mental status 1
• Severe immunocompromise or neutropenia 1
• Signs suggesting necrotizing fasciitis: severe pain out of proportion to examination, skin anesthesia, rapid progression, "wooden-hard" subcutaneous tissues, or bullous changes 1

Penicillin Allergy Considerations

• For patients with non-severe penicillin allergy, cephalexin remains an option—cross-reactivity between penicillins and cephalosporins is only 2-4% 1
• For severe penicillin allergy (anaphylaxis, angioedema, urticaria), use clindamycin 300-450 mg orally every 6 hours if local MRSA resistance is <10% 1

Reassessment Timeline

• Mandatory reassessment in 24-48 hours to verify clinical response, as treatment failure rates of 21% have been reported with some oral regimens 1
• If no improvement or worsening occurs, reassess for MRSA risk factors, necrotizing infection, or misdiagnosis 1