What is the recommended first-line antibiotic regimen for outpatient treatment of cellulitis?

Outpatient Treatment for Cellulitis

First-Line Antibiotic Regimen

For typical uncomplicated cellulitis, beta-lactam monotherapy is the standard of care and should be your first choice, with cephalexin 500 mg four times daily or dicloxacillin 250-500 mg every 6 hours for 5 days. 1

Beta-lactam monotherapy achieves a 96% success rate in treating typical cellulitis, confirming that MRSA coverage is unnecessary in most cases. 1 The Infectious Diseases Society of America explicitly recommends against routinely adding MRSA coverage for typical nonpurulent cellulitis, as MRSA is an uncommon cause even in high-prevalence settings. 1

Recommended Oral Agents

Choose from these beta-lactam options for uncomplicated cellulitis:

• Cephalexin 500 mg four times daily 1
• Dicloxacillin 250-500 mg every 6 hours 1
• Amoxicillin (appropriate dosing) 1
• Amoxicillin-clavulanate 875/125 mg twice daily (particularly for bite-associated cellulitis) 1
• 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 represents a significant departure from traditional 7-14 day courses, which are no longer necessary for uncomplicated cases. 1 A landmark randomized controlled trial demonstrated that 5 days of levofloxacin achieved 98% clinical resolution with no relapse by 28 days, identical to 10-day therapy. 2

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
• Known MRSA colonization or evidence of MRSA infection elsewhere 1
• Systemic inflammatory response syndrome (SIRS) 1
• Failure to respond to beta-lactam therapy after 48 hours 1

MRSA-Active Regimens When Indicated

If MRSA coverage is needed, use one of these options:

• Clindamycin monotherapy 300-450 mg every 6 hours (covers both streptococci and MRSA, avoiding need for combination therapy) 1
• Trimethoprim-sulfamethoxazole PLUS a beta-lactam (e.g., cephalexin) 1
• Doxycycline 100 mg twice daily PLUS a beta-lactam 1

Critical caveat: Never use doxycycline or trimethoprim-sulfamethoxazole as monotherapy for typical cellulitis, as their activity against beta-hemolytic streptococci is unreliable. 1 In a Hawaii study with 62% MRSA prevalence, trimethoprim-sulfamethoxazole achieved 91% success versus 74% for cephalexin, but this was in a high MRSA-prevalence setting where purulent infections were likely included. 3

Special Populations and Situations

Penicillin/Cephalosporin Allergy

For patients allergic to both penicillins and cephalosporins:

• Clindamycin 300-450 mg every 6 hours is optimal, providing single-agent coverage for both streptococci and MRSA 1
• Use clindamycin only if local MRSA clindamycin resistance rates are <10% 1
• Alternative: Levofloxacin 500 mg daily (reserve for beta-lactam allergies; lacks reliable MRSA coverage) 1

Bite-Associated Cellulitis

Amoxicillin-clavulanate 875/125 mg twice daily provides single-agent coverage for polymicrobial oral flora from human or animal bites. 1 Do not add trimethoprim-sulfamethoxazole to this regimen, as it has poor anaerobic activity. 1

Diabetic Foot Cellulitis

Consider broader coverage with amoxicillin-clavulanate or second/third-generation cephalosporins (cefuroxime, ceftriaxone) for moderate diabetic foot infections. 1

Essential Adjunctive Measures

These non-antibiotic interventions are critical but often neglected:

• Elevate the affected extremity above heart level for at least 30 minutes three times daily to promote gravitational drainage 1
• Examine interdigital toe spaces for tinea pedis, fissuring, or maceration; treating these eradicates colonization and reduces recurrence 1
• Address predisposing conditions: venous insufficiency, lymphedema, chronic edema, eczema 1
• Consider systemic corticosteroids (prednisone 40 mg daily for 7 days) in non-diabetic adults, though evidence is limited 1

Indications for Hospitalization

Admit patients with any of the following: 1

• Systemic inflammatory response syndrome (SIRS): 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
• Suspected necrotizing fasciitis (severe pain out of proportion to exam, skin anesthesia, rapid progression, gas in tissue, bullous changes) 1

Common Pitfalls to Avoid

• Do not reflexively add MRSA coverage for typical nonpurulent cellulitis without specific risk factors—this represents overtreatment and increases resistance 1
• Do not continue ineffective antibiotics beyond 48 hours—progression despite appropriate therapy indicates resistant organisms or deeper infection 1
• Do not use combination therapy (e.g., cephalexin plus trimethoprim-sulfamethoxazole) for pure cellulitis without abscess, ulcer, or purulent drainage—it provides no additional benefit 1
• Do not extend treatment beyond 5 days unless clinical improvement has not occurred 1
• Assess for abscess with ultrasound if there is any clinical uncertainty, as purulent collections require incision and drainage plus MRSA-active antibiotics 1

Reassessment and Follow-Up

Mandatory reassessment in 24-48 hours is essential to verify clinical response, as treatment failure rates of 21% have been reported with some oral regimens. 1 If cellulitis is spreading despite appropriate antibiotics, immediately reassess for MRSA risk factors, necrotizing infection, or misdiagnosis. 1