What is the appropriate empiric antibiotic regimen for cellulitis in an adult, including recommendations for uncomplicated non‑purulent cases, MRSA risk factors, and severe infections?

Treatment of Cellulitis

For typical uncomplicated cellulitis, prescribe a beta-lactam antibiotic (cephalexin 500 mg every 6 hours or dicloxacillin 250–500 mg every 6 hours) for exactly 5 days, and add MRSA coverage only when specific risk factors are present—not routinely. 1

First-Line Therapy for Uncomplicated Cellulitis

Beta-lactam monotherapy achieves 96% clinical success in typical nonpurulent cellulitis because the primary pathogens are beta-hemolytic streptococci (especially Streptococcus pyogenes) and methicillin-sensitive Staphylococcus aureus. 1, 2

Recommended Oral Regimens (Choose One)

• Cephalexin 500 mg orally every 6 hours for 5 days 1
• Dicloxacillin 250–500 mg orally every 6 hours for 5 days 1
• Amoxicillin 500 mg orally three times daily for 5 days 1
• Penicillin V 250–500 mg orally four times daily for 5 days 1

Treatment Duration

• Treat for exactly 5 days if clinical improvement occurs (reduced warmth, tenderness, improving erythema, no fever). 1
• Extend only if symptoms have not improved within this 5-day period—do not automatically extend to 7–14 days based on residual erythema alone. 1
• High-quality randomized controlled trial evidence confirms 5-day courses are as effective as 10-day courses for uncomplicated cellulitis. 1

When to Add MRSA Coverage

MRSA is an uncommon cause of typical cellulitis even in high-prevalence settings, so routine MRSA coverage is unnecessary and promotes resistance. 1, 2

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

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

MRSA-Active Oral Regimens (When Risk Factors Present)

Option 1: Clindamycin Monotherapy

• Clindamycin 300–450 mg orally every 6 hours for 5 days provides single-agent coverage for both streptococci and MRSA. 1, 3
• Use only if local MRSA clindamycin resistance is <10%—if resistance exceeds this threshold, choose an alternative regimen. 1, 3

Option 2: Combination Therapy

• Trimethoprim-sulfamethoxazole (TMP-SMX) 1–2 double-strength tablets twice daily PLUS a beta-lactam (cephalexin or amoxicillin) for 5 days 1
• Doxycycline 100 mg orally twice daily PLUS a beta-lactam (cephalexin or amoxicillin) for 5 days 1
• Never use doxycycline or TMP-SMX as monotherapy for typical cellulitis—they lack reliable activity against beta-hemolytic streptococci. 1

Option 3: Linezolid

• Linezolid 600 mg orally twice daily for 5 days is effective but expensive; reserve for complicated cases or when other options are unsuitable. 1, 4

Inpatient Management and IV Therapy

Hospitalization Criteria

Admit patients with cellulitis when any of the following are present:

• Systemic inflammatory response syndrome (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 or bullae) 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 (preferred IV beta-lactam) 1
• Nafcillin or oxacillin 2 g IV every 6 hours (alternative) 1

For Complicated Cellulitis with MRSA Risk Factors:

• Vancomycin 15–20 mg/kg IV every 8–12 hours (target trough 15–20 mg/L) 1, 3
• Linezolid 600 mg IV twice daily (A-I evidence) 1, 4
• Daptomycin 4 mg/kg IV once daily (A-I evidence) 1, 5
• Clindamycin 600 mg IV every 8 hours (only if local MRSA resistance <10%; A-III evidence) 1

For Severe Cellulitis with Systemic Toxicity or Suspected Necrotizing Infection:

• 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
• Duration: 7–14 days for complicated infections, individualized based on clinical response 1

Special Populations

Pediatric Dosing (1–17 Years)

Oral Therapy for Uncomplicated Cellulitis:

• Cephalexin 25–50 mg/kg/day divided every 6 hours for 5 days 1
• Amoxicillin 25–50 mg/kg/day divided every 8 hours for 5 days 1

When MRSA Coverage Needed:

• Clindamycin 10–13 mg/kg/dose every 6–8 hours (max 40 mg/kg/day; only if local resistance <10%) 1
• TMP-SMX 4–6 mg/kg/dose (TMP component) twice daily PLUS a beta-lactam 1
• Doxycycline 2 mg/kg twice daily (max 100 mg/dose) PLUS a beta-lactam (only for children ≥8 years and <45 kg) 1
• Never use doxycycline in children <8 years—risk of permanent tooth discoloration and impaired bone growth. 1

IV Therapy for Hospitalized Children:

• Vancomycin 15 mg/kg IV every 6 hours (first-line; A-II evidence) 1
• Clindamycin 10–13 mg/kg/dose IV every 6–8 hours (if stable, no bacteremia, local resistance <10%) 1
• Linezolid 10 mg/kg IV every 8 hours for children <12 years; 600 mg IV twice daily for children ≥12 years 1, 4

Penicillin Allergy Management

• For non-immediate hypersensitivity (e.g., maculopapular rash), cephalexin remains acceptable—cross-reactivity is only 2–4%. 1
• For true penicillin allergy, use clindamycin 300–450 mg orally every 6 hours (if local MRSA resistance <10%). 1
• Avoid cephalexin in confirmed immediate-type amoxicillin allergy due to identical R1 side chains. 1

Bite-Related Cellulitis

• Amoxicillin-clavulanate 875/125 mg twice daily provides single-agent coverage for polymicrobial oral flora in human or animal bite-associated cellulitis. 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; treat these conditions to eradicate colonization and reduce recurrent infection. 1
• Address predisposing conditions including venous insufficiency, lymphedema, chronic edema, obesity, and eczema to lower recurrence risk. 1
• Consider systemic corticosteroids (prednisone 40 mg daily for 7 days) in non-diabetic adults, though evidence is limited. 1

Critical Pitfalls to Avoid

• Do not add MRSA coverage routinely for typical nonpurulent cellulitis without specific risk factors—this overtreats ~96% of cases and promotes resistance. 1, 2, 6
• Do not automatically extend therapy to 7–10 days based solely on residual erythema; extend only if warmth, tenderness, or erythema have not improved after 5 days. 1
• Do not use doxycycline or TMP-SMX as monotherapy for typical cellulitis—they lack reliable activity against beta-hemolytic streptococci. 1
• Do not delay surgical consultation when signs of necrotizing infection (severe pain out of proportion, skin anesthesia, rapid progression, "wooden-hard" tissue) are present—these infections progress rapidly and require debridement. 1
• Do not treat simple abscesses with antibiotics alone—incision and drainage is the primary treatment, with antibiotics serving only an adjunctive role when specific risk factors are present. 1, 3

Reassessment and Follow-Up

• Reassess patients within 24–48 hours to verify clinical response; treatment failure rates of ~21% have been reported with some oral regimens. 1
• If no improvement after 48–72 hours, consider resistant organisms (MRSA), undrained abscess, deeper infection (necrotizing fasciitis, osteomyelitis), or alternative diagnoses. 1