What are the recommended antibiotics for treating lower extremity cellulitis?

Recommended Antibiotic for Lower Extremity Cellulitis

For typical uncomplicated lower extremity cellulitis, use beta-lactam monotherapy with cephalexin 500 mg orally every 6 hours for 5 days—MRSA coverage is unnecessary in 96% of cases and should only be added when specific risk factors are present. 1

First-Line Treatment Algorithm

Standard Beta-Lactam Monotherapy (Preferred)

• Cephalexin 500 mg orally every 6 hours is the preferred first-line agent, providing effective coverage against streptococci and methicillin-sensitive S. aureus 1
• Alternative oral beta-lactams include:
  • Dicloxacillin 250-500 mg every 6 hours 1
  • Amoxicillin-clavulanate 875/125 mg twice daily 1
  • Penicillin or amoxicillin 1
• Beta-lactam monotherapy succeeds in 96% of patients, confirming that MRSA coverage is usually unnecessary 1

For Hospitalized Patients Requiring IV Therapy

• Cefazolin 1-2 g IV every 8 hours is the preferred parenteral beta-lactam 1
• Nafcillin 1-2 g IV every 4-6 hours is an alternative 2
• Continue IV therapy until clinical improvement, then transition to oral cephalexin or dicloxacillin 1

Treatment Duration

• Treat for 5 days if clinical improvement occurs—extension beyond 5 days is only necessary if symptoms have not improved 1, 3
• Five-day courses are as effective as 10-day courses for uncomplicated cellulitis 1, 3
• Reassess within 24-48 hours to verify clinical response 1

When to Add MRSA Coverage (Specific Risk Factors Only)

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

• Penetrating trauma or injection drug use 1
• Purulent drainage or exudate visible 1
• Evidence of MRSA infection elsewhere or known nasal MRSA colonization 1
• Systemic inflammatory response syndrome (SIRS): fever, tachycardia, hypotension, altered mental status 1
• Failure to respond to beta-lactam therapy after 48-72 hours 1

MRSA Coverage Options When Indicated

For outpatients requiring MRSA coverage: 1

• Clindamycin 300-450 mg orally three times daily (covers both streptococci and MRSA, avoiding need for combination therapy) 1
• Trimethoprim-sulfamethoxazole (TMP-SMX) 1-2 double-strength tablets twice daily PLUS a beta-lactam (cephalexin, penicillin, or amoxicillin)—never use TMP-SMX as monotherapy due to inadequate streptococcal coverage 1
• Doxycycline 100 mg orally twice daily PLUS a beta-lactam 1

For hospitalized patients with complicated cellulitis requiring MRSA coverage: 1

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

Severe Infections Requiring Broad-Spectrum Coverage

For patients with signs of systemic toxicity, rapid progression, or suspected necrotizing fasciitis, use mandatory broad-spectrum combination therapy: 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 combinations: vancomycin PLUS a carbapenem (meropenem 1 g IV every 8 hours) 1
• Alternative combinations: vancomycin PLUS ceftriaxone 2 g IV daily and metronidazole 500 mg IV every 8 hours 1
• Duration: 7-14 days guided by clinical response 1

Critical Evidence Supporting Beta-Lactam Monotherapy

• The Infectious Diseases Society of America recommends beta-lactam monotherapy as the standard of care for typical uncomplicated cellulitis, as MRSA is an uncommon cause 1
• A randomized controlled trial demonstrated that combination therapy with TMP-SMX plus cephalexin is no more efficacious than cephalexin alone in pure cellulitis without abscess, ulcer, or purulent drainage (85% cure rate vs 82%, risk difference 2.7%, P=0.66) 4
• Adding MRSA coverage to beta-lactam therapy provides no additional benefit in typical cases 1
• However, in high MRSA-prevalence areas, antibiotics without CA-MRSA activity had 4.22 times higher odds of treatment failure (95% CI 2.25-7.92) when MRSA was present 5

Essential Adjunctive Measures

• Elevate the affected extremity to promote gravity drainage of edema and inflammatory substances 1
• Examine interdigital toe spaces carefully for tinea pedis, fissuring, scaling, or maceration—treat if present 1
• Treat predisposing conditions including venous insufficiency, lymphedema, eczema, and obesity 1
• Consider systemic corticosteroids (prednisone 40 mg daily for 7 days) in non-diabetic adults only—avoid in diabetic patients 1

Common Pitfalls to Avoid

• Do not routinely add MRSA coverage for typical cellulitis—MRSA is an unusual cause and coverage is unnecessary in 96% of cases 1
• Do not use TMP-SMX or doxycycline as monotherapy—these lack reliable activity against beta-hemolytic streptococci and must be combined with a beta-lactam 1
• Do not extend treatment beyond 5 days automatically—only extend if clinical improvement has not occurred 1
• Do not obtain blood cultures for typical cellulitis—they are positive in only 5% of cases; reserve for patients with severe systemic features, malignancy, neutropenia, or severe immunodeficiency 1
• Do not delay switching therapy if no improvement after 48-72 hours—add empiric MRSA coverage immediately 1

Hospitalization Criteria

Admit patients with any of the following: 1

• SIRS criteria (fever, altered mental status, hemodynamic instability)
• Concern for deeper or necrotizing infection
• Severe immunocompromise or neutropenia
• Failure of outpatient treatment after 24-48 hours
• Poor adherence to outpatient therapy

Special Considerations for Diabetic Patients

• 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 diabetic patients despite evidence showing benefit in non-diabetic adults 1
• Elevation of the affected extremity is especially important in patients with heart failure or diabetes 1