What is the first‑line treatment for an otherwise healthy adult with acute non‑purulent cellulitis of the lower extremity without risk factors for methicillin‑resistant Staphylococcus aureus?

First-Line Treatment for Uncomplicated Non-Purulent Lower Extremity Cellulitis

For an otherwise healthy adult with acute non-purulent cellulitis of the lower extremity without MRSA risk factors, prescribe cephalexin 500 mg orally every 6 hours (or dicloxacillin 250-500 mg every 6 hours) for exactly 5 days—MRSA coverage is unnecessary and represents overtreatment in this scenario. 1

Why Beta-Lactam Monotherapy Is the Standard of Care

• Beta-lactam monotherapy achieves 96% clinical success in typical non-purulent cellulitis because the causative organisms are overwhelmingly beta-hemolytic streptococci (especially Streptococcus pyogenes) and methicillin-sensitive Staphylococcus aureus 1, 2, 3

• MRSA is an uncommon cause of typical cellulitis even in high-prevalence settings, making routine MRSA coverage both unnecessary and potentially harmful by promoting antimicrobial resistance 1, 3

• Recommended oral beta-lactam options include cephalexin 500 mg every 6 hours, dicloxacillin 250-500 mg every 6 hours, amoxicillin 500 mg three times daily, or penicillin V 250-500 mg four times daily 1

Treatment Duration: The 5-Day Rule

• Treat for exactly 5 days if clinical improvement occurs (resolution of warmth and tenderness, improving erythema, absence of fever); extend only if these symptoms have not improved 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

• Traditional 7-14 day regimens are unnecessary for uncomplicated cases and promote antimicrobial resistance without improving outcomes 1

When to Add MRSA Coverage (and When NOT To)

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

• Penetrating trauma or injection drug use 1
• Visible purulent drainage or exudate at the infection site 1
• Known MRSA colonization or prior MRSA infection 1
• Systemic inflammatory response syndrome (fever >38°C, heart rate >90 bpm, respiratory rate >24/min) 1
• Lack of clinical response to beta-lactam therapy after 48-72 hours 1

In the absence of these factors, adding MRSA coverage provides no benefit and was specifically disproven in a randomized controlled trial showing that cephalexin plus trimethoprim-sulfamethoxazole was no more effective than cephalexin alone for non-purulent cellulitis 1, 4

MRSA-Active Regimens (When Risk Factors Are Present)

If MRSA coverage is required, choose one of these options:

• 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

• Trimethoprim-sulfamethoxazole 1-2 double-strength tablets twice daily PLUS a beta-lactam (cephalexin or amoxicillin) ensures dual coverage 1

• Doxycycline 100 mg orally twice daily PLUS a beta-lactam is another combination option 1

Critical pitfall: Never use doxycycline or trimethoprim-sulfamethoxazole as monotherapy for typical cellulitis—they lack reliable activity against beta-hemolytic streptococci, the predominant pathogens 1

Essential Adjunctive Measures

• Elevate the affected leg 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, 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 lower recurrence risk 1

Hospitalization Criteria

Admit patients when any of the following are present:

• Systemic inflammatory response syndrome (fever, tachycardia, hypotension, altered mental status) 1
• Signs of deeper or necrotizing infection (severe pain out of proportion to exam, skin anesthesia, rapid progression, "wooden-hard" tissue, gas or bullae) 1
• Severe immunocompromise or neutropenia 1
• Failure of outpatient therapy after 24-48 hours 1

For hospitalized patients without MRSA risk factors, use cefazolin 1-2 g IV every 8 hours 1, 6

For severe cellulitis with systemic toxicity, use vancomycin 15-20 mg/kg IV every 8-12 hours PLUS piperacillin-tazobactam 3.375-4.5 g IV every 6 hours 1

Common Pitfalls to Avoid

• Do not add MRSA coverage reflexively for typical non-purulent cellulitis without the specified risk factors—this overtreats 96% of cases and drives resistance 1, 3

• 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 reassessment—evaluate patients within 24-48 hours to confirm clinical response, as treatment failure rates of approximately 21% have been reported with some oral regimens 1

• Do not use combination therapy when monotherapy is appropriate—the randomized trial by Pallin et al. definitively showed no benefit of adding trimethoprim-sulfamethoxazole to cephalexin for non-purulent cellulitis 4