What is the first-line management for an otherwise healthy adult with uncomplicated acute cellulitis of the leg?

First-Line Management of Uncomplicated Acute Leg Cellulitis

For an otherwise healthy adult with uncomplicated acute cellulitis of the leg, beta-lactam monotherapy with oral cephalexin 500 mg four times daily or dicloxacillin 250-500 mg every 6 hours for 5 days is the standard of care, achieving 96% clinical success without requiring MRSA coverage. 1, 2

Antibiotic Selection Algorithm

Step 1: Confirm this is typical nonpurulent cellulitis

• Acute onset of erythema, warmth, swelling, and tenderness without purulent drainage, abscess, or penetrating trauma 1, 3
• No systemic toxicity (fever >38°C, hypotension, altered mental status) 1
• No MRSA risk factors: no injection drug use, no visible purulent drainage, no known MRSA colonization 1

Step 2: Initiate beta-lactam monotherapy

• First-line options: Cephalexin 500 mg orally four times daily OR dicloxacillin 250-500 mg every 6 hours 1, 2
• Alternative beta-lactams: Amoxicillin, penicillin V 250-500 mg four times daily, or amoxicillin-clavulanate 875/125 mg twice daily 1
• Duration: Exactly 5 days if clinical improvement occurs; extend only if warmth, tenderness, or erythema have not improved 1, 2, 4

The evidence supporting this approach is robust: beta-lactam monotherapy succeeds in 96% of typical cellulitis cases because the primary pathogens are beta-hemolytic streptococci (especially Streptococcus pyogenes) and methicillin-sensitive Staphylococcus aureus, not MRSA 1, 2, 3. A landmark randomized controlled trial demonstrated that adding trimethoprim-sulfamethoxazole to cephalexin provides no additional benefit in pure cellulitis without abscess or purulent drainage 5.

Treatment Duration Evidence

The 5-day treatment course is supported by high-quality randomized controlled trial evidence. A double-blind, placebo-controlled trial of 87 patients with uncomplicated cellulitis showed that 5 days of levofloxacin achieved 98% clinical resolution at 14 days with no relapse by 28 days—identical to 10 days of therapy 4. Traditional 7-14 day courses are no longer necessary for uncomplicated cases 1.

Essential Adjunctive Measures

Beyond antibiotics, physical measures accelerate recovery:

• Elevation: Raise the affected leg 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, scaling, or maceration; treating these eradicates colonization and reduces recurrent infection 1
• Address predisposing conditions: venous insufficiency, lymphedema, chronic edema 1, 2

When to Add MRSA Coverage (NOT Routine)

MRSA coverage is NOT needed for typical nonpurulent cellulitis, even in high-prevalence settings. 1, 3 Add MRSA-active antibiotics ONLY when specific risk factors are present:

• Penetrating trauma or injection drug use 1
• Purulent drainage or exudate 1
• Known MRSA colonization or prior MRSA infection 1
• Systemic inflammatory response syndrome (SIRS) 1
• Failure to respond to beta-lactam after 48-72 hours 1

If MRSA coverage is needed: Use clindamycin 300-450 mg orally every 6 hours (provides single-agent coverage for both streptococci and MRSA if local resistance <10%) OR combination therapy with trimethoprim-sulfamethoxazole 1-2 double-strength tablets twice daily PLUS a beta-lactam 1

Penicillin Allergy Management

For patients reporting penicillin allergy, cross-reactivity with cephalosporins is only 2-4%, so cephalexin remains an option except in confirmed immediate-type amoxicillin allergy 2. Alternative: clindamycin 300-450 mg every 6 hours if local MRSA resistance <10% 1

Common Pitfalls to Avoid

• Do not reflexively add MRSA coverage to all cellulitis cases; this represents overtreatment and increases antibiotic resistance without improving outcomes 1, 3
• Do not extend treatment to 10-14 days based on residual erythema alone; some inflammation persists even after bacterial eradication 1
• Do not use doxycycline or trimethoprim-sulfamethoxazole as monotherapy for typical cellulitis; their activity against beta-hemolytic streptococci is unreliable 1
• Reassess within 24-48 hours to verify clinical response, as treatment failure rates of 21% have been reported with some oral regimens 1

Indications for Hospitalization

Hospitalize if any of the following are present:

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

For severe cellulitis requiring hospitalization, initiate vancomycin 15-20 mg/kg IV every 8-12 hours PLUS piperacillin-tazobactam 3.375-4.5 g IV every 6 hours 1, 2