What is the recommended treatment for uncomplicated superficial cellulitis in an adult without known drug allergies?

Treatment for Superficial Cellulitis

For uncomplicated superficial 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 if clinical improvement occurs. 1

First-Line Antibiotic Selection

Beta-lactam monotherapy is the standard of care for typical nonpurulent cellulitis, achieving a 96% clinical success rate because the primary pathogens are beta-hemolytic streptococci (especially Streptococcus pyogenes) and methicillin-sensitive Staphylococcus aureus. 1, 2, 3

Recommended oral beta-lactam options include:

• Cephalexin 500 mg orally every 6 hours 1, 4
• 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
• Amoxicillin-clavulanate 875/125 mg orally twice daily 1, 4

Cefdinir is also an acceptable alternative cephalosporin for typical cellulitis, though it is not specifically listed as a first-line agent in the most recent IDSA guidelines. 4

Treatment Duration

Treat for exactly 5 days if warmth and tenderness have resolved, erythema is improving, and the patient is afebrile. 1 High-quality randomized controlled trial evidence demonstrates that 5-day courses are as effective as 10-day courses for uncomplicated cellulitis. 1, 4 Extend treatment only if symptoms have not improved within this 5-day timeframe. 1, 4

Traditional 7-14 day courses are no longer necessary for uncomplicated cases and represent overtreatment that increases antibiotic resistance without improving outcomes. 1

When MRSA Coverage Is NOT Needed

MRSA is an uncommon cause of typical nonpurulent cellulitis even in high-prevalence settings, and routine MRSA coverage provides no additional benefit. 1, 3 The landmark JAMA trial by Moran et al. demonstrated that adding trimethoprim-sulfamethoxazole to cephalexin did not improve clinical cure rates in uncomplicated cellulitis (83.5% vs 85.5%, difference -2.0%, 95% CI -9.7% to 5.7%). 5

Do not add MRSA coverage for typical superficial cellulitis without specific risk factors, as this represents overtreatment. 1

When to Add MRSA Coverage

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

• Penetrating trauma or injection drug use 1, 4
• Purulent drainage or exudate visible at the infection site 1, 4
• Known MRSA colonization or prior MRSA infection 1
• Systemic inflammatory response syndrome (fever >38°C, tachycardia >90 bpm, tachypnea >24 breaths/min) 1
• Failure to respond to beta-lactam therapy after 48-72 hours 1

When MRSA coverage is indicated, 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, 4
• Trimethoprim-sulfamethoxazole 1-2 double-strength tablets twice daily PLUS a beta-lactam (cephalexin or amoxicillin) 1
• Doxycycline 100 mg orally twice daily PLUS a beta-lactam 1

However, in areas with high community-acquired MRSA prevalence (>60% of S. aureus isolates), some observational data suggest empiric MRSA coverage with trimethoprim-sulfamethoxazole or clindamycin may improve outcomes. 6 This conflicts with the IDSA guideline recommendation and the JAMA randomized trial, so clinical judgment is required in high-prevalence settings.

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, scaling, or maceration and treat if present, as this eradicates colonization and reduces recurrent infection risk. 1, 7
• Treat predisposing conditions including venous insufficiency, lymphedema, chronic edema, and eczema. 1, 4, 7

Critical Pitfalls to Avoid

• Do not use doxycycline or trimethoprim-sulfamethoxazole as monotherapy for typical cellulitis, as they lack reliable activity against beta-hemolytic streptococci. 1
• Do not reflexively extend treatment to 7-10 days based on residual erythema alone, as some inflammation persists even after bacterial eradication. 1
• Do not add MRSA coverage routinely without the specific risk factors listed above, as this promotes resistance without improving outcomes in 96% of cases. 1, 5

When to Hospitalize

Hospitalize patients with any of the following:

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

For hospitalized patients requiring IV therapy, use cefazolin 1-2 g IV every 8 hours or nafcillin 2 g IV every 6 hours for uncomplicated cases. 1 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