Treating Cellulitis

First-Line Treatment for Uncomplicated Cellulitis

Beta-lactam monotherapy is the standard of care for typical uncomplicated cellulitis in otherwise healthy adults, achieving 96% clinical success. 1

Recommended Oral Regimens (Mild-to-Moderate Infection)

Cephalexin 500 mg orally every 6 hours for 5 days is the preferred first-line oral beta-lactam 1
Dicloxacillin 250-500 mg orally every 6 hours for 5 days provides excellent streptococcal and MSSA coverage 1
Amoxicillin is an acceptable alternative beta-lactam option 1
Treatment duration is exactly 5 days if clinical improvement occurs; extend only if warmth, tenderness, or erythema have not improved 1

MRSA coverage is NOT routinely necessary because MRSA is an uncommon cause of typical nonpurulent cellulitis even in high-prevalence settings. 1, 2 Adding MRSA coverage to beta-lactam therapy provides no additional benefit in typical cases without specific risk factors. 1

When to Add MRSA Coverage

Add MRSA-active antibiotics only when specific risk factors are present:

Purulent drainage or exudate at the infection site 1, 3
Penetrating trauma or injection drug use 1, 3
Known MRSA colonization or prior MRSA infection 1, 3
Systemic inflammatory response syndrome (SIRS) – fever >38°C, tachycardia >90 bpm, tachypnea >24 breaths/min 1
Failure to respond to beta-lactam therapy after 48-72 hours 1, 3

Oral MRSA-Active Regimens

For purulent cellulitis requiring MRSA coverage:

Clindamycin 300-450 mg orally every 6 hours for 5 days provides single-agent coverage for both streptococci and MRSA, but use only if local MRSA clindamycin resistance rates are <10% 1, 3
Trimethoprim-sulfamethoxazole (TMP-SMX) 1-2 double-strength tablets twice daily PLUS a beta-lactam (cephalexin or amoxicillin) for 5 days 1, 3
Doxycycline 100 mg orally twice daily PLUS a beta-lactam for 5 days 1, 3

Critical pitfall: Never use doxycycline or TMP-SMX as monotherapy for typical cellulitis because they lack reliable activity against beta-hemolytic streptococci, which cause the vast majority of cases. 1, 3

Penicillin Allergy Alternatives

For patients with penicillin allergy:

Clindamycin 300-450 mg orally every 6 hours is the preferred alternative because it provides single-agent coverage for both streptococci and MRSA (if local resistance <10%) 1
Levofloxacin 500 mg daily for 5 days can be used in patients with beta-lactam allergies, though fluoroquinolones should be reserved for this indication 1
Cephalexin remains acceptable in non-immediate penicillin allergy because cross-reactivity is only 2-4%; avoid in confirmed immediate-type reactions (anaphylaxis, angioedema, urticaria) 1

Intravenous Therapy for Moderate-to-Severe Cellulitis Requiring Hospitalization

Indications for Hospitalization

Admit patients with any of the following:

Systemic inflammatory response syndrome (SIRS) – fever, tachycardia, hypotension, altered mental status 1
Signs of necrotizing infection – severe pain out of proportion to exam, skin anesthesia, rapid progression, "wooden-hard" tissue, gas in tissue 1
Severe immunocompromise or neutropenia 1
Failure of outpatient therapy after 24-48 hours 1

IV Antibiotic Regimens

For uncomplicated cellulitis requiring hospitalization (no MRSA risk factors):

Cefazolin 1-2 g IV every 8 hours is the preferred IV beta-lactam 1
Nafcillin 2 g IV every 6 hours or oxacillin 2 g IV every 6 hours are alternatives 1

For complicated cellulitis requiring MRSA coverage:

Vancomycin 15-20 mg/kg IV every 8-12 hours (target trough 15-20 mg/L) is first-line with A-I evidence 1, 3
Linezolid 600 mg IV twice daily is an equally effective alternative (A-I evidence) 1
Daptomycin 4 mg/kg IV once daily is another option (A-I evidence) 1
Clindamycin 600 mg IV every 8 hours if local MRSA resistance <10% (A-III evidence) 1

For severe cellulitis with systemic toxicity or suspected necrotizing fasciitis:

Vancomycin 15-20 mg/kg IV every 8-12 hours PLUS piperacillin-tazobactam 3.375-4.5 g IV every 6 hours provides mandatory broad-spectrum coverage 1, 3
Alternative combinations: vancomycin PLUS a carbapenem or vancomycin PLUS ceftriaxone 2 g IV daily and metronidazole 500 mg IV every 8 hours 1

Treatment duration for hospitalized patients is 7-14 days, individualized based on clinical response, with reassessment at 5 days. 1

Transition to Oral Therapy

Patients can transition to oral antibiotics once clinical improvement is demonstrated, typically after a minimum of 4 days of IV treatment:

Cephalexin, dicloxacillin, or clindamycin are appropriate oral options 1
Clindamycin alone or in combination with a beta-lactam can be used for continued MRSA coverage orally 1

Essential Adjunctive Measures

Elevate the affected extremity above heart level for at least 30 minutes three times daily to promote gravity drainage of edema and inflammatory substances 1
Examine interdigital toe spaces for tinea pedis, fissuring, scaling, or maceration and treat to eradicate colonization and reduce recurrent infection 1
Address predisposing conditions including venous insufficiency, lymphedema, chronic edema, obesity, and eczema 1
Consider systemic corticosteroids (prednisone 40 mg daily for 7 days) in non-diabetic adults, though evidence is limited 1

Common Pitfalls to Avoid

Do not routinely add MRSA coverage for typical nonpurulent cellulitis without specific risk factors—this represents overtreatment in 96% of cases 1, 2
Do not extend treatment to 7-10 days based on residual erythema alone; inflammation may persist for days to weeks after bacterial eradication 1
Do not use beta-lactam antibiotics alone when MRSA is suspected or confirmed—they have no activity against methicillin-resistant organisms 3
Do not delay surgical consultation if any signs of necrotizing infection are present—these infections progress rapidly and require debridement 1
Reassess patients within 24-48 hours to verify clinical response, as treatment failure rates of 21% have been reported with some oral regimens 1

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