What is the best antibiotic for treating leg cellulitis?

Best Antibiotic for Leg Cellulitis

For typical uncomplicated leg cellulitis, use a beta-lactam antibiotic such as cephalexin 500 mg four times daily or dicloxacillin 250-500 mg every 6 hours for 5 days, as this approach succeeds in 96% of patients and MRSA coverage is unnecessary in most cases. 1

First-Line Oral Antibiotics

Beta-lactam monotherapy is the standard of care for typical nonpurulent leg cellulitis, targeting the primary pathogens: beta-hemolytic streptococci (especially Streptococcus pyogenes) and methicillin-sensitive Staphylococcus aureus. 1

Recommended oral agents include:

• Cephalexin 500 mg every 6 hours (preferred first-line agent) 1, 2
• Dicloxacillin 250-500 mg every 6 hours 1, 2
• Amoxicillin (appropriate for streptococcal coverage) 1
• Amoxicillin-clavulanate 875/125 mg twice daily (provides broader coverage including beta-lactamase-producing organisms) 1, 2
• Penicillin V 250-500 mg four times daily 1

Treatment Duration

Treat for exactly 5 days if clinical improvement occurs; extend only if symptoms have not improved within this timeframe. 1 This recommendation is supported by high-quality randomized controlled trial evidence showing that 5-day courses are as effective as 10-day courses for uncomplicated cellulitis. 1, 3

When MRSA Coverage is NOT Needed

MRSA is an uncommon cause of typical cellulitis, even in hospitals with high MRSA prevalence, and routine MRSA coverage represents overtreatment. 1 Beta-lactam treatment succeeds in 96% of patients with typical cellulitis, confirming that MRSA coverage is usually unnecessary. 1

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, 4
• Evidence of MRSA infection elsewhere or known nasal MRSA colonization 1
• Systemic inflammatory response syndrome (SIRS) with fever, tachycardia, or hypotension 1
• Failure to respond to beta-lactam therapy after 48-72 hours 1, 2

MRSA-Active Regimens (when indicated):

Oral options:

• Clindamycin 300-450 mg every 6 hours (covers both streptococci and MRSA, avoiding need for combination therapy) 1, 5
• Trimethoprim-sulfamethoxazole (TMP-SMX) 1-2 DS tablets twice daily PLUS a beta-lactam (cephalexin or amoxicillin) 1, 4
• Doxycycline 100 mg twice daily PLUS a beta-lactam 1

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

Intravenous Options for Hospitalized Patients

For patients requiring hospitalization due to systemic toxicity, hemodynamic instability, or inability to tolerate oral therapy: 1

Standard IV therapy:

• Cefazolin 1-2 g IV every 8 hours (preferred IV beta-lactam for uncomplicated cellulitis) 1
• Nafcillin or oxacillin 2 g IV every 6 hours (alternatives) 1

For complicated cellulitis requiring MRSA coverage:

• Vancomycin 15-20 mg/kg IV every 8-12 hours (first-line, A-I evidence) 1
• Linezolid 600 mg IV twice daily (equally effective alternative, A-I evidence) 1
• Daptomycin 4 mg/kg IV once daily (A-I evidence) 1
• Clindamycin 600 mg IV every 8 hours (if local MRSA resistance <10%, A-III evidence) 1, 5

Severe Cellulitis with Systemic Toxicity

For patients with signs of systemic toxicity, rapid progression, or suspected necrotizing fasciitis, mandatory broad-spectrum combination therapy is required: 1

• Vancomycin 15-20 mg/kg IV every 8-12 hours PLUS piperacillin-tazobactam 3.375-4.5 g IV every 6 hours 1
• Alternative: Linezolid PLUS piperacillin-tazobactam 1
• Alternative: Vancomycin PLUS a carbapenem (meropenem 1 g IV every 8 hours) 1

Essential Adjunctive Measures

Beyond antibiotics, these interventions hasten improvement: 1

• Elevate the affected leg 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, maceration) and treat if present, as this eradicates colonization and reduces recurrence 1
• Address predisposing conditions: venous insufficiency, lymphedema, chronic edema, obesity 1
• Consider systemic corticosteroids (prednisone 40 mg daily for 7 days) in non-diabetic adults, though evidence is limited 1

Common Pitfalls to Avoid

• Do not routinely add MRSA coverage for typical nonpurulent cellulitis without specific risk factors 1
• Do not extend treatment beyond 5 days automatically—only extend if clinical improvement has not occurred 1
• Do not use doxycycline or TMP-SMX as monotherapy for typical cellulitis due to inadequate streptococcal coverage 1
• Do not delay reassessment—evaluate outpatients within 24-48 hours to ensure clinical response 1, 2
• Do not use systemic corticosteroids in diabetic patients despite potential benefit in non-diabetics 1

Hospitalization Criteria

Admit patients with: 1

• SIRS criteria (fever, altered mental status, hemodynamic instability)
• Concern for deeper or necrotizing infection (severe pain out of proportion to exam, skin anesthesia, rapid progression, gas in tissue, bullous changes)
• Severe immunocompromise or neutropenia
• Failure of outpatient treatment after 24-48 hours
• Poor adherence to outpatient therapy

Special Populations

Diabetic patients: Require longer treatment duration compared to non-diabetic patients, with median treatment extending beyond the standard 5-day course. 1 Avoid systemic corticosteroids in diabetics. 1

Penicillin-allergic patients: Clindamycin 300-450 mg every 6 hours is the optimal choice, providing single-agent coverage for both streptococci and MRSA. 1, 2, 5

Prevention of Recurrent Cellulitis

For patients with 3-4 episodes per year despite treating predisposing factors, consider prophylactic antibiotics: 1

• Oral penicillin V 250 mg twice daily for 4-52 weeks
• Oral erythromycin 250 mg twice daily
• Intramuscular benzathine penicillin every 2-4 weeks