What are the first and second line treatments for cellulitis?

First and Second Line Treatment for Cellulitis

Beta-lactam monotherapy (penicillin, amoxicillin, dicloxacillin, or cephalexin) for 5 days is the first-line treatment for typical uncomplicated cellulitis, with a 96% success rate, and MRSA coverage should NOT be added routinely. 1, 2

First-Line Treatment Algorithm

For Typical Nonpurulent Cellulitis (Most Common Presentation)

Oral regimens (choose one):

• Cephalexin 500 mg orally every 6 hours 1, 2
• Dicloxacillin 250-500 mg orally every 6 hours 1, 2
• Amoxicillin (standard dosing) 1, 2
• Penicillin V 250-500 mg orally four times daily 1, 2

Treatment duration: Exactly 5 days if clinical improvement occurs (warmth and tenderness resolved, erythema improving, patient afebrile); extend ONLY if no improvement within this timeframe 1, 2

Why this works: Beta-hemolytic streptococci (especially Streptococcus pyogenes) cause the majority of typical cellulitis cases, and MRSA is an uncommon cause even in high-prevalence settings 1, 3, 4

For Penicillin-Allergic Patients (First-Line Alternative)

Clindamycin 300-450 mg orally every 6 hours for 5 days provides single-agent coverage for both streptococci and MRSA, eliminating the need for combination therapy 1, 2

Alternative options for penicillin allergy:

• Levofloxacin 500 mg daily (reserve for beta-lactam allergies, lacks reliable MRSA coverage) 2
• Erythromycin (if local resistance is low) 2

Critical caveat: Use clindamycin ONLY if local MRSA clindamycin resistance rates are <10% 1

Second-Line Treatment: When to Add MRSA Coverage

Add MRSA-active therapy ONLY when specific risk factors are present: 1, 2

• Penetrating trauma or injection drug use
• Purulent drainage or exudate visible
• Evidence of MRSA infection elsewhere or nasal MRSA colonization
• Systemic inflammatory response syndrome (SIRS): fever >38°C, tachycardia >90 bpm, tachypnea >24 rpm
• Athletes, prisoners, military recruits, long-term care facility residents, men who have sex with men 3

Second-Line Oral Regimens for MRSA Coverage

Option 1: Clindamycin monotherapy

• Clindamycin 300-450 mg orally every 6 hours for 5 days 1, 2
• Covers both streptococci and MRSA with a single agent 1

Option 2: Combination therapy

• Trimethoprim-sulfamethoxazole (1-2 double-strength tablets twice daily) PLUS a beta-lactam (cephalexin or dicloxacillin) 1, 2
• Doxycycline 100 mg orally twice daily PLUS a beta-lactam 1, 2

Critical warning: NEVER use doxycycline or trimethoprim-sulfamethoxazole as monotherapy for typical cellulitis—their activity against beta-hemolytic streptococci is unreliable 1, 2

Option 3: Linezolid

• Linezolid 600 mg orally twice daily 1, 2
• Expensive; reserve for complicated cases 1

Inpatient/IV Treatment for Severe Cellulitis

For Uncomplicated Cellulitis Requiring Hospitalization (Without MRSA Risk Factors)

Cefazolin 1-2 g IV every 8 hours is the preferred IV beta-lactam 1

Alternative: Oxacillin 2 g IV every 6 hours or nafcillin 2 g IV every 6 hours 1

For Severe Cellulitis with Systemic Toxicity or Suspected Necrotizing Fasciitis

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:

• Linezolid 600 mg IV twice daily PLUS piperacillin-tazobactam 1
• Vancomycin PLUS a carbapenem (meropenem 1 g IV every 8 hours) 1
• Vancomycin PLUS ceftriaxone 2 g IV daily and metronidazole 500 mg IV every 8 hours 1

Duration: 7-10 days for severe infections, reassessing at 5 days 1

For Complicated Cellulitis with MRSA Risk Factors (Hospitalized)

First-line IV options (all A-I evidence): 1

• Vancomycin 15-20 mg/kg IV every 8-12 hours
• Linezolid 600 mg IV twice daily
• Daptomycin 4 mg/kg IV once daily
• Clindamycin 600 mg IV every 8 hours (only if local resistance <10%)

Essential Adjunctive Measures (Often Neglected)

Elevation of the affected extremity above heart level for at least 30 minutes three times daily hastens improvement by promoting gravity drainage of edema and inflammatory substances 1, 2

Examine interdigital toe spaces for tinea pedis, fissuring, scaling, or maceration—treating these eradicates colonization and reduces recurrent infection risk 1, 2

Treat predisposing conditions: 1, 2

• Venous insufficiency with compression stockings (once acute infection resolves)
• Lymphedema management
• Chronic edema control
• Toe web abnormalities

Consider systemic corticosteroids (prednisone 40 mg daily for 7 days) in non-diabetic adults to hasten resolution, though evidence is limited 1, 2

Common Pitfalls to Avoid

Do NOT reflexively add MRSA coverage for typical nonpurulent cellulitis simply because the patient is hospitalized or because MRSA prevalence is high in your institution—beta-lactam monotherapy succeeds in 96% of cases 1

Do NOT extend treatment to 7-10 days based on tradition or residual erythema alone—5 days is sufficient if clinical improvement has occurred (warmth/tenderness resolved, erythema improving) 1, 2

Do NOT use doxycycline or trimethoprim-sulfamethoxazole alone for typical cellulitis—they lack reliable streptococcal coverage and must be combined with a beta-lactam 1, 2

Do NOT continue ineffective antibiotics beyond 48 hours—progression despite appropriate therapy indicates either resistant organisms or a deeper/different infection (consider necrotizing fasciitis, abscess, or misdiagnosis) 1

When to Escalate or Reassess

Mandatory reassessment at 24-48 hours to verify clinical response, as treatment failure rates of 21% have been reported with some oral regimens 1

Warning signs requiring emergent surgical consultation: 1

• Severe pain out of proportion to examination
• Skin anesthesia or "wooden-hard" subcutaneous tissues
• Rapid progression or bullous changes
• Gas in tissue on imaging
• Systemic toxicity (hypotension, confusion, altered mental status)

If spreading despite appropriate antibiotics: Reassess for MRSA risk factors, necrotizing infection, or misdiagnosis; switch to vancomycin or linezolid if MRSA suspected or systemic toxicity present 1