How should I treat non‑purulent cellulitis in an adult, including first‑line oral antibiotics, alternatives for penicillin or cephalosporin allergy, MRSA coverage if risk factors are present, and when to use intravenous therapy?

Treatment of Nonpurulent Cellulitis

For typical nonpurulent cellulitis in adults, prescribe a beta-lactam antibiotic (cephalexin 500 mg every 6 hours or dicloxacillin 250–500 mg every 6 hours) for exactly 5 days, reserving MRSA coverage only for patients with specific risk factors such as penetrating trauma, purulent drainage, injection drug use, or failure to respond after 48–72 hours. 1

First-Line Oral Antibiotic Therapy

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 Agents (choose one):

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

Treatment duration is exactly 5 days if clinical improvement occurs (reduced warmth, tenderness, improving erythema, no fever); extend only if symptoms have not improved within this timeframe. 1 High-quality randomized controlled trial evidence demonstrates that 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 nonpurulent cellulitis even in high-prevalence settings, so routine MRSA coverage is unnecessary and represents overtreatment. 1, 2

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

• Penetrating trauma or injection drug use 1, 3
• Visible purulent drainage or exudate 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 indicated):

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
• Use ONLY if local MRSA clindamycin resistance is <10% 1

Option 2: Combination therapy

• Trimethoprim-sulfamethoxazole 1–2 double-strength tablets twice daily PLUS cephalexin 500 mg every 6 hours 1
• Doxycycline 100 mg twice daily PLUS a beta-lactam (cephalexin or amoxicillin) 1

Critical pitfall: Never use doxycycline or trimethoprim-sulfamethoxazole as monotherapy for typical cellulitis because they lack reliable activity against beta-hemolytic streptococci, the predominant pathogens. 1

Penicillin or Cephalosporin Allergy Management

For non-immediate penicillin allergy (e.g., maculopapular rash), cephalosporins remain acceptable because cross-reactivity is only 2–4%. 1

For true penicillin allergy:

• Clindamycin 300–450 mg orally every 6 hours (if local MRSA clindamycin resistance <10%) 1
• Levofloxacin 750 mg daily (reserve for beta-lactam allergies; lacks reliable MRSA coverage) 1

For cephalosporin allergy:

• Penicillin V 250–500 mg orally four times daily provides excellent streptococcal coverage 1
• Clindamycin 300–450 mg orally every 6 hours (if local resistance permits) 1

Intravenous Therapy Indications

Hospitalize and Initiate IV Antibiotics When:

• Systemic inflammatory response syndrome (fever, tachycardia, hypotension, altered mental status) 1
• Signs of deeper or necrotizing infection (severe pain out of proportion to exam, skin anesthesia, rapid progression, "wooden-hard" tissue, gas in tissue, bullous changes) 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 (alternatives) 1

For cellulitis with MRSA risk factors:

• Vancomycin 15–20 mg/kg IV every 8–12 hours (target trough 15–20 mg/L) 1
• Linezolid 600 mg IV twice daily (A-I evidence) 1
• Daptomycin 4 mg/kg IV once daily (A-I evidence) 1
• 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 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 for complicated infections is 7–14 days, individualized based on clinical response. 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 these conditions to eradicate colonization and reduce recurrent infection. 1
• Address predisposing conditions including venous insufficiency, lymphedema, chronic edema, obesity, and eczema. 1

Critical Pitfalls to Avoid

• Do not add MRSA coverage reflexively for typical nonpurulent cellulitis without the specified risk factors—this overtreats 96% of cases and promotes antimicrobial resistance. 1
• 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 delay surgical consultation when any signs of necrotizing infection are present (severe pain out of proportion, rapid progression, skin anesthesia, bullous changes, gas in tissue). 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

Special Populations

For injection drug users (even if stable and nontoxic-appearing):

• Empiric MRSA coverage is mandatory because this population has high CA-MRSA prevalence. 3
• Clindamycin 300–450 mg orally three times daily OR trimethoprim-sulfamethoxazole 1–2 double-strength tablets twice daily PLUS amoxicillin 500 mg three times daily for 5–10 days. 3
• Never use beta-lactam monotherapy in injection drug users, even if stable—this will fail. 3

For diabetic foot infections:

• Diabetic foot infections are polymicrobial and require broader coverage than simple cellulitis. 1
• Mild infections: amoxicillin-clavulanate, levofloxacin, or trimethoprim-sulfamethoxazole 1
• Moderate infections: ceftriaxone, ampicillin-sulbactam, or ertapenem 1
• Severe infections: piperacillin-tazobactam, imipenem-cilastatin, or vancomycin plus ceftazidime 1