What is the next best step for a patient with lower leg cellulitis who is not responding to Augmentin (amoxicillin-clavulanate)?

Switch to MRSA-Active Antibiotic Immediately

For lower leg cellulitis failing Augmentin, add empirical MRSA coverage immediately with either clindamycin 300-450 mg orally every 6 hours, or trimethoprim-sulfamethoxazole (TMP-SMX) 1-2 double-strength tablets twice daily PLUS continue a beta-lactam (cephalexin 500 mg every 6 hours), for 5 days if clinical improvement occurs. 1, 2

Why Augmentin Failure Demands MRSA Coverage

• The Infectious Diseases Society of America explicitly recommends adding empirical MRSA coverage in patients with nonpurulent cellulitis who do not respond to β-lactam therapy 2
• Antibiotics without CA-MRSA activity have 4.22 times higher odds of treatment failure (95% CI 2.25-7.92) in MRSA-prevalent areas 2
• While beta-lactam monotherapy succeeds in 96% of typical cellulitis cases, your patient represents the 4% who fail—making MRSA the most likely culprit 1

Immediate Action Algorithm

Step 1: Assess Severity Markers

• Check for fever >38°C, heart rate >90, respiratory rate >24, WBC >12,000 or <4,000 2
• Examine for purulent drainage, skin anesthesia, severe pain out of proportion to exam, bullous changes, or gas in tissue 1, 2
• Evaluate for systemic toxicity: hypotension, confusion, altered mental status 1, 2

Step 2: Outpatient vs. Inpatient Decision

• If stable without systemic signs: Switch to oral MRSA-active regimen outpatient 1, 2
• If SIRS criteria present or systemic toxicity: Hospitalize immediately and start IV vancomycin 15-20 mg/kg every 8-12 hours 1, 2

Step 3: Choose Outpatient Oral Regimen

• Option A (Preferred): Clindamycin 300-450 mg orally every 6 hours—covers both streptococci and MRSA as monotherapy 1, 2
• Option B: TMP-SMX 1-2 DS tablets twice daily PLUS cephalexin 500 mg every 6 hours—combination provides dual coverage 1, 2
• Option C: Doxycycline 100 mg twice daily PLUS cephalexin 500 mg every 6 hours 1, 2

Critical Caveats About Monotherapy

• Never use TMP-SMX or doxycycline alone—they lack reliable streptococcal coverage, which remains the primary pathogen even in treatment failures 1, 2
• Clindamycin is the only oral agent that can be used as monotherapy because it covers both streptococci and MRSA 1, 2
• Only use clindamycin if local MRSA clindamycin resistance rates are <10% 1

Treatment Duration After Switch

• Continue the new regimen for 5 days if clinical improvement occurs, extending only if symptoms have not improved within this timeframe 1, 2
• Reassess within 24-48 hours to verify clinical improvement—do not wait beyond 48-72 hours of failed therapy as this increases morbidity 2

When to Hospitalize Instead

Mandatory hospitalization criteria:

• Systemic inflammatory response syndrome (SIRS): fever, tachycardia, tachypnea, abnormal WBC 1, 2
• Hemodynamic instability or hypotension 1, 2
• Altered mental status or confusion 1, 2
• Concern for necrotizing fasciitis: severe pain out of proportion, skin anesthesia, rapid progression, gas in tissue, bullous changes 1, 2
• Failure of outpatient treatment after 24-48 hours 1

For hospitalized patients requiring IV therapy:

• Vancomycin 15-20 mg/kg IV every 8-12 hours is first-line (A-I evidence) 1, 2
• Alternative IV options: linezolid 600 mg IV twice daily, daptomycin 4 mg/kg IV once daily 1, 2

Alternative Diagnoses to Consider

If no improvement with MRSA coverage after 48 hours, reassess for:

• Abscess requiring incision and drainage—obtain ultrasound if clinical uncertainty 1, 2
• Deep vein thrombosis mimicking cellulitis 2
• Necrotizing infection requiring surgical debridement 1, 2
• Atypical organisms like gram-negative rods (Proteus mirabilis has been reported in treatment-resistant leg cellulitis) 3

Essential Adjunctive Measures

• Elevate the affected leg—this is critical and often neglected, promoting gravity drainage of edema and inflammatory substances 1, 2
• Examine interdigital toe spaces for tinea pedis, fissuring, scaling, or maceration—treat if present to reduce recurrence 1, 2
• Address predisposing conditions: venous insufficiency, lymphedema, chronic edema, eczema 1, 2

Common Pitfall to Avoid

• Do not simply increase the Augmentin dose or switch to high-dose amoxicillin-clavulanate (2000/125 mg twice daily)—while this can overcome organisms with elevated MICs, it does not provide MRSA coverage, which is the most likely cause of beta-lactam failure 1, 2
• Do not delay switching therapy—waiting beyond 48-72 hours of failed therapy increases morbidity 2