What antibiotic is recommended for uncomplicated skin cellulitis in an otherwise healthy individual?

Antibiotic Treatment for Uncomplicated Skin Cellulitis

For uncomplicated skin cellulitis in an otherwise healthy individual, use a beta-lactam antibiotic such as cephalexin 500 mg orally every 6 hours for 5 days, as beta-lactam monotherapy is successful in 96% of cases and MRSA coverage is unnecessary for typical nonpurulent cellulitis. 1

First-Line Antibiotic Selection

Beta-lactam monotherapy is the standard of care for typical uncomplicated cellulitis. 1 The Infectious Diseases Society of America recommends the following oral agents as appropriate first-line options 1:

• Cephalexin 500 mg every 6 hours (preferred first-line agent) 1
• Dicloxacillin 250-500 mg every 6 hours 1
• Amoxicillin (standard dosing) 1
• Amoxicillin-clavulanate 875/125 mg twice daily 1
• Penicillin V 250-500 mg four times daily 1

These agents provide excellent coverage against beta-hemolytic streptococci (especially Streptococcus pyogenes) and methicillin-sensitive Staphylococcus aureus, which are the primary pathogens in typical cellulitis 1, 2.

Treatment Duration

Treat for exactly 5 days if clinical improvement has occurred; extend only if symptoms have not improved within this timeframe. 1 High-quality randomized controlled trial evidence demonstrates that 5-day courses are as effective as 10-day courses for uncomplicated cellulitis 1, 3. In a landmark double-blind, placebo-controlled trial, clinical resolution at 14 days with no relapse by 28 days occurred in 98% of patients receiving 5 days of levofloxacin compared to 98% receiving 10 days 3.

When MRSA Coverage Is NOT Needed

MRSA is an uncommon cause of typical cellulitis, even in high-prevalence settings, and routine MRSA coverage is unnecessary. 1 Beta-lactam treatment is successful in 96% of patients, confirming that MRSA coverage is usually unnecessary 1. Adding MRSA coverage to beta-lactam therapy provides no additional benefit in typical cases 1.

Two high-quality randomized controlled trials definitively demonstrate this:

• Cephalexin plus trimethoprim-sulfamethoxazole versus cephalexin alone showed no difference in clinical cure (85% vs 82%, P=0.66) 4
• A larger multicenter trial showed clinical cure in 83.5% with combination therapy versus 85.5% with cephalexin alone (difference -2.0%, 95% CI -9.7% to 5.7%, P=0.50) 5

When to Add MRSA Coverage

Add MRSA-active antibiotics ONLY when specific risk factors are present 1:

• Penetrating trauma or injection drug use 1
• Purulent drainage or exudate 1
• Evidence of MRSA infection elsewhere or known nasal MRSA colonization 1
• Systemic inflammatory response syndrome (SIRS) with fever, tachycardia, or hypotension 1

MRSA Coverage Options

When MRSA coverage is indicated, use one of these regimens 1:

• 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
• Trimethoprim-sulfamethoxazole 1-2 double-strength tablets twice daily PLUS a beta-lactam (cephalexin, amoxicillin, or penicillin) 1
• Doxycycline 100 mg orally twice daily PLUS a beta-lactam 1

Critical caveat: Never use trimethoprim-sulfamethoxazole or doxycycline as monotherapy for typical cellulitis, as their activity against beta-hemolytic streptococci is unreliable 1, 6.

Essential Adjunctive Measures

Beyond antibiotics, these interventions hasten improvement 1:

• Elevate the affected extremity above heart level for at least 30 minutes three times daily to promote gravity drainage of edema 1
• Examine interdigital toe spaces for tinea pedis, fissuring, scaling, or maceration, and treat these to eradicate colonization and reduce recurrent infection 1
• Address predisposing conditions including venous insufficiency, lymphedema, chronic edema, eczema, and obesity 1

Penicillin Allergy Considerations

For patients with penicillin allergy 1, 6:

• Clindamycin 300-450 mg every 6 hours is the preferred option (if local resistance <10%) 1
• Cephalexin can still be used in patients with non-immediate penicillin allergy, as cross-reactivity is only 2-4% 1
• Avoid cephalexin in patients with confirmed immediate-type amoxicillin allergy, as they share identical R1 side chains 1

Common Pitfalls to Avoid

• Do not routinely add MRSA coverage for typical cellulitis without specific risk factors—this represents overtreatment and increases antibiotic resistance 1
• Do not extend treatment to 10-14 days based on residual erythema alone, as some inflammation persists even after bacterial eradication 1
• Do not use fluoroquinolones (levofloxacin, moxifloxacin) as first-line therapy—reserve these for patients with beta-lactam allergies to minimize resistance 1
• Do not use doxycycline or trimethoprim-sulfamethoxazole as monotherapy, as they lack reliable streptococcal coverage 1

When to Reassess or Hospitalize

Reassess within 24-48 hours to verify clinical response, as treatment failure rates of 21% have been reported with some oral regimens 1. Hospitalize if any of the following are present 1:

• Systemic inflammatory response syndrome (fever >38°C, tachycardia >90 bpm, hypotension)
• Altered mental status or confusion
• Severe immunocompromise or neutropenia
• Concern for deeper or necrotizing infection (severe pain out of proportion to examination, skin anesthesia, rapid progression, "wooden-hard" subcutaneous tissues)