What are the recommended antibiotics for cellulitis of the legs?

Recommended Antibiotics for Cellulitis of the Legs

For typical uncomplicated leg cellulitis, use beta-lactam monotherapy with cephalexin 500 mg every 6 hours or dicloxacillin 250-500 mg every 6 hours for 5 days, as this achieves 96% success rates 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, as streptococci (primarily Streptococcus pyogenes) and methicillin-sensitive Staphylococcus aureus cause the vast majority of cases. 1, 2

Preferred Oral Agents:

• Cephalexin 500 mg every 6 hours - most commonly recommended first-line agent 1, 3
• Dicloxacillin 250-500 mg every 6 hours - excellent streptococcal and MSSA coverage 1
• Amoxicillin - appropriate for typical cellulitis 1
• Amoxicillin-clavulanate 875/125 mg twice daily - provides broader coverage including beta-lactamase producers 1
• Penicillin - adequate for streptococcal coverage 1

Treatment Duration

Treat for exactly 5 days if clinical improvement occurs; extend only if symptoms have not improved within this timeframe. 1, 4 A randomized controlled trial demonstrated that 5 days of levofloxacin achieved 98% success rates, identical to 10-day courses, making traditional 7-14 day regimens obsolete for uncomplicated cases. 4

When to Add MRSA Coverage (Critical Decision Points)

Do NOT routinely add MRSA coverage - even in hospitals with high MRSA prevalence, MRSA remains an uncommon cause of typical nonpurulent cellulitis. 1 Adding MRSA coverage to beta-lactam therapy provides no additional benefit in typical cases. 1

Add MRSA-Active Antibiotics ONLY When These Specific Risk Factors Are Present:

• Penetrating trauma or injection drug use 1, 5
• Purulent drainage or exudate visible 1, 5
• Evidence of MRSA infection elsewhere or known nasal MRSA colonization 1
• Systemic inflammatory response syndrome (SIRS): fever >38°C, tachycardia >90 bpm, hypotension, or altered mental status 1
• Failure to respond to beta-lactam therapy after 48-72 hours 1, 5

MRSA-Active Oral Regimens When Indicated:

• Clindamycin 300-450 mg every 6 hours - covers both streptococci and MRSA, avoiding need for combination therapy (use only if local resistance <10%) 1
• Trimethoprim-sulfamethoxazole (TMP-SMX) 1-2 double-strength tablets twice daily PLUS a beta-lactam (cephalexin, amoxicillin, or penicillin) - never use TMP-SMX as monotherapy due to unreliable streptococcal coverage 1, 5
• Doxycycline 100 mg twice daily PLUS a beta-lactam - tetracyclines lack reliable activity against beta-hemolytic streptococci and require combination 1

In a retrospective cohort study from a high MRSA-prevalence area, antibiotics without community-associated MRSA activity had 4.22 times higher odds of treatment failure (95% CI 2.25-7.92). 5 However, this applies only to areas with documented high MRSA prevalence and patients with specific risk factors.

Intravenous Antibiotics for Hospitalized Patients

Indications for Hospitalization:

• SIRS criteria (fever, tachycardia, hypotension, altered mental status) 1
• Severe immunocompromise or neutropenia 1
• Concern for necrotizing fasciitis or deeper infection 1
• Failure of outpatient therapy after 24-48 hours 1

Standard IV Therapy for Uncomplicated Cellulitis Requiring Hospitalization:

• Cefazolin 1-2 g IV every 8 hours - preferred IV beta-lactam 1
• Oxacillin 2 g IV every 6 hours - alternative 1

These remain appropriate even in the inpatient setting if cellulitis is nonpurulent and lacks MRSA risk factors, with 96% success rates. 1

IV Therapy When MRSA Coverage Required:

• Vancomycin 15-20 mg/kg IV every 8-12 hours - first-line for complicated cellulitis (A-I evidence) 1, 6
• Linezolid 600 mg IV twice daily - equally effective alternative (A-I evidence) 1, 6
• Daptomycin 4 mg/kg IV once daily - alternative (A-I evidence) 1
• Clindamycin 600 mg IV every 8 hours - if local MRSA resistance <10% (A-III evidence) 1

Severe Cellulitis with Systemic Toxicity 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: Vancomycin PLUS a carbapenem (meropenem 1 g IV every 8 hours) 1
• Alternative: Vancomycin PLUS ceftriaxone 2 g IV daily and metronidazole 500 mg IV every 8 hours 1

Treat for 7-14 days depending on severity and clinical response. 1

Essential Adjunctive Measures

• Elevate the affected leg - promotes gravity drainage of edema and hastens improvement 1, 3
• Examine interdigital toe spaces for tinea pedis, fissuring, scaling, or maceration - treat these to reduce recurrence 1
• Address predisposing conditions: venous insufficiency, lymphedema, obesity, eczema 1
• Consider systemic corticosteroids (prednisone 40 mg daily for 7 days) in non-diabetic adults, though evidence is limited - avoid in diabetic patients 1

Prophylaxis for Recurrent Cellulitis

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

• Oral penicillin or erythromycin twice daily for 4-52 weeks 1
• Intramuscular benzathine penicillin every 2-4 weeks 1

A randomized controlled trial showed penicillin V prophylaxis reduced recurrence risk by 47% (HR 0.53,95% CI 0.26-1.07), with number needed to treat of 8 to prevent one episode. 7

Critical Pitfalls to Avoid

• Do not reflexively add MRSA coverage simply because the patient is hospitalized or because MRSA prevalence is high in your institution - typical cellulitis remains predominantly streptococcal 1
• Do not use doxycycline or TMP-SMX as monotherapy for typical cellulitis - they lack reliable streptococcal coverage 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, 4
• Do not obtain blood cultures routinely - they are positive in only 5% of typical cellulitis cases; reserve for patients with severe systemic features, malignancy, or neutropenia 1
• Reassess within 24-48 hours for outpatients to verify clinical response - treatment failure rates of 21% have been reported with some regimens 1, 5