What are the recommended antibiotics for non-purulent (not containing pus) cellulitis?

Recommended Antibiotics for Non-Purulent Cellulitis

For typical non-purulent cellulitis, beta-lactam monotherapy with oral penicillin, amoxicillin, cephalexin, or dicloxacillin is the standard of care and achieves 96% success rates—MRSA coverage is NOT needed and should not be added routinely. 1, 2, 3

First-Line Treatment Algorithm

Standard Beta-Lactam Options (Choose One)

• Cephalexin 500 mg orally four times daily for 5 days if clinical improvement occurs 2, 4
• Dicloxacillin 250-500 mg orally every 6 hours for 5 days 2
• Amoxicillin 500 mg orally three times daily for 5 days 2
• Penicillin V 250-500 mg orally four times daily for 5 days 2

Treatment duration: 5 days if improvement occurs; extend ONLY if symptoms have not improved within this timeframe. 1, 2

Why Beta-Lactam Monotherapy Works

• β-hemolytic streptococci (primarily Streptococcus pyogenes) cause the majority of non-purulent cellulitis cases 1, 3
• Methicillin-sensitive Staphylococcus aureus (MSSA) accounts for most remaining cases 3
• MRSA is an uncommon cause of typical non-purulent cellulitis, even in high-prevalence settings 1, 2, 3
• A landmark randomized controlled trial demonstrated that adding trimethoprim-sulfamethoxazole (TMP-SMX) to cephalexin provided no additional benefit for non-purulent cellulitis without abscess (85% cure vs 82% cure, risk difference 2.7%, p=0.66) 5

When NOT to Add MRSA Coverage

Do not add MRSA-active antibiotics for typical non-purulent cellulitis lacking these specific risk factors: 1, 2

• Penetrating trauma or injection drug use
• Purulent drainage or exudate present
• Known MRSA colonization or concurrent MRSA infection elsewhere
• Failure to respond to beta-lactam therapy after 48-72 hours
• Systemic inflammatory response syndrome (SIRS) with fever, tachycardia, or hypotension

Alternative Options for Beta-Lactam Allergies

If Penicillin/Cephalosporin Allergy

Clindamycin 300-450 mg orally every 6 hours for 5 days is the optimal single-agent alternative, providing coverage for both streptococci and MRSA 1, 2, 6

• Use ONLY if local MRSA clindamycin resistance rates are <10% 1, 2
• This eliminates the need for combination therapy 2

Other Non-Penicillin Options (Less Preferred)

• Levofloxacin 500 mg orally daily for 5 days (reserve for specific allergy scenarios, not first-line) 2
• Doxycycline 100 mg orally twice daily PLUS a beta-lactam if MRSA coverage needed (doxycycline alone is inadequate due to unreliable streptococcal activity) 1, 2, 6
• TMP-SMX 1-2 double-strength tablets orally twice daily PLUS a beta-lactam if MRSA coverage needed 1, 6

Hospitalized Patients Requiring IV Therapy

For non-purulent cellulitis requiring hospitalization (due to inability to take oral medications, not severity):

• Cefazolin 1-2 g IV every 8 hours is the preferred IV beta-lactam 1, 2
• Oxacillin 2 g IV every 6 hours is an alternative 2
• Transition to oral therapy once clinical improvement demonstrated 2

For complicated 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, 2
• Alternative: Linezolid 600 mg IV twice daily plus piperacillin-tazobactam 1, 2
• Duration: 7-14 days based on clinical response 1

Critical Pitfalls to Avoid

Do not reflexively add MRSA coverage simply because MRSA prevalence is high in your region—the pathogen causing non-purulent cellulitis differs from purulent infections 1, 2, 3

Do not use doxycycline or TMP-SMX as monotherapy for typical cellulitis, as their activity against β-hemolytic streptococci is unreliable and will result in treatment failure 1, 2, 6

Do not continue ineffective antibiotics beyond 48 hours—if the patient is worsening or not improving, reassess for MRSA risk factors, necrotizing infection, or misdiagnosis 2

Do not treat for 10-14 days routinely—5 days is sufficient if clinical improvement occurs, and longer courses increase adverse effects without improving outcomes 1, 2

Adjunctive Measures That Accelerate Recovery

• Elevate the affected extremity to promote gravitational drainage of edema 2
• Examine and treat interdigital toe web spaces for tinea pedis, fissuring, or maceration to reduce recurrence 2
• Address predisposing conditions including venous insufficiency, lymphedema, and chronic edema 2
• Consider systemic corticosteroids (prednisone 40 mg daily for 7 days) in non-diabetic adults, though evidence is limited 2