What antibiotics are recommended for treating uncomplicated cellulitis?

Antibiotic Treatment for Uncomplicated Cellulitis

For typical uncomplicated cellulitis, beta-lactam monotherapy is the standard of care and is successful in 96% of patients—MRSA coverage is unnecessary in most cases. 1

First-Line Antibiotic Selection

Oral beta-lactams are the preferred agents for uncomplicated cellulitis, targeting streptococci (the primary pathogen) and methicillin-sensitive S. aureus. 1

Recommended oral regimens include:

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

For hospitalized patients requiring IV therapy:

• Cefazolin 1-2 g IV every 8 hours (preferred IV agent) 1
• Nafcillin 2 g IV every 6 hours 1
• Oxacillin 2 g IV every 6 hours 1

Treatment Duration

Treat for exactly 5 days if clinical improvement occurs; extend only if symptoms have not improved within this timeframe. 1 This represents a major shift from traditional 7-14 day courses, as high-quality randomized controlled trial evidence demonstrates that 5-day courses are equally effective as 10-day courses for uncomplicated cellulitis. 2

When to Add MRSA Coverage

MRSA is an uncommon cause of typical nonpurulent cellulitis, even in high-prevalence settings, and routine coverage is NOT recommended. 1 Add MRSA-active antibiotics ONLY when specific risk factors are present:

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

MRSA-Active Regimens When Indicated

Oral options for outpatients:

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

IV options for hospitalized patients:

• 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, 3
• Daptomycin 4 mg/kg IV once daily (A-I evidence) 1
• Clindamycin 600 mg IV every 8 hours (only if local MRSA resistance <10%) 1

Critical Pitfalls to Avoid

Never use doxycycline or trimethoprim-sulfamethoxazole as monotherapy for typical cellulitis—their activity against beta-hemolytic streptococci is unreliable, and streptococci are the primary pathogens in most cases. 1 These agents must always be combined with a beta-lactam when treating nonpurulent cellulitis. 1

Do not reflexively add MRSA coverage simply because a patient is hospitalized or because community MRSA prevalence is high. 1 Beta-lactam monotherapy remains appropriate for typical cellulitis even in the inpatient setting if no specific MRSA risk factors are present. 1

Fluoroquinolones (levofloxacin, moxifloxacin) are approved for uncomplicated cellulitis but lack adequate MRSA coverage and should be reserved for patients with beta-lactam allergies. 4

Severe Cellulitis Requiring Broad-Spectrum Coverage

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

• 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: Linezolid PLUS piperacillin-tazobactam 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

Treat for 7-14 days in these severe cases, guided by clinical response. 1

Essential Adjunctive Measures

Elevation of the affected extremity hastens improvement by promoting gravity drainage of edema and inflammatory substances—this simple intervention is often neglected but critical. 1

Examine interdigital toe spaces carefully for tinea pedis, fissuring, scaling, or maceration—treating these eradicates colonization and reduces recurrent infection risk. 1

Address predisposing conditions including venous insufficiency, lymphedema, chronic edema, eczema, and obesity to minimize recurrence. 1

Consider systemic corticosteroids (prednisone 40 mg daily for 7 days) in non-diabetic adults to potentially hasten resolution, though evidence is limited. 1 Avoid corticosteroids in diabetic patients. 1

Hospitalization Criteria

Admit patients with any of the following:

• SIRS criteria (fever >38°C, tachycardia >90 bpm, tachypnea >24 rpm) 1
• Hypotension or hemodynamic instability 1
• Altered mental status or confusion 1
• Severe immunocompromise or neutropenia 1
• Concern for deeper or necrotizing infection 1
• Failure of outpatient treatment after 24-48 hours 1

Monitoring and Follow-Up

Reassess outpatients within 24-48 hours to verify clinical response. 1 If no improvement with appropriate first-line antibiotics, consider resistant organisms (add MRSA coverage), cellulitis mimickers (venous stasis dermatitis, contact dermatitis, DVT), or underlying complications (abscess requiring drainage, necrotizing infection). 1, 5

Blood cultures are positive in only 5% of cases and are unnecessary for typical cellulitis, but obtain them in patients with severe systemic features, malignancy, neutropenia, or unusual predisposing factors. 1