A patient with left elbow cellulitis has completed a 14‑day course of oral cephalexin 500 mg three times daily without improvement; should I add another medication or change therapy?

Treatment Failure: Switch from Cephalexin to MRSA-Active Therapy

You should discontinue cephalexin and switch to an MRSA-active regimen immediately, as treatment failure after 14 days of appropriate beta-lactam therapy strongly suggests either MRSA involvement or a complication requiring different management. 1

Why Cephalexin Has Failed

• Cephalexin is ineffective against MRSA, which may be the causative pathogen in your patient's case given the lack of response to 14 days of therapy 1
• First-generation cephalosporins like cephalexin are also completely ineffective for Lyme disease, which can mimic cellulitis and should be considered if the patient is in an endemic area 2, 3
• Treatment failure after 48-72 hours of appropriate beta-lactam therapy mandates reassessment for MRSA risk factors or complications 1

Immediate Recommended Action

Switch to clindamycin 300-450 mg orally every 6 hours for 5 days as your first-line oral option, provided local MRSA clindamycin resistance rates are <10%. 1 This provides single-agent coverage for both streptococci and MRSA without requiring combination therapy. 1

Alternative Oral Regimens if Clindamycin Resistance is High

• Trimethoprim-sulfamethoxazole (TMP-SMX) 1-2 double-strength tablets twice daily PLUS cephalexin 500 mg four times daily for dual coverage 1
• Doxycycline 100 mg twice daily PLUS cephalexin 500 mg four times daily for 5 days 1

Critical caveat: Never use TMP-SMX or doxycycline as monotherapy for typical cellulitis, as both have unreliable activity against beta-hemolytic streptococci, which remain the primary pathogens in most cases. 1, 4

When to Hospitalize for IV Therapy

Admit for IV vancomycin 15-20 mg/kg every 8-12 hours if any of the following are present: 1

• Systemic inflammatory response syndrome (fever >38°C, tachycardia >90 bpm, tachypnea >24 rpm)
• Hypotension or altered mental status
• Rapid progression despite oral therapy
• Severe immunocompromise

Rule Out Complications Before Switching Antibiotics

Obtain ultrasound imaging to exclude abscess formation, as any purulent collection requires incision and drainage as primary treatment, with antibiotics playing only a subsidiary role. 1 The addition of MRSA coverage to beta-lactam therapy provides no benefit if an undrained abscess is present. 1

Assess for necrotizing fasciitis warning signs: 1

• Severe pain out of proportion to examination findings
• Skin anesthesia or "wooden-hard" subcutaneous tissues
• Bullous changes or skin necrosis
• Gas in tissue on imaging

If any of these are present, obtain emergent surgical consultation and initiate broad-spectrum IV combination therapy (vancomycin PLUS piperacillin-tazobactam). 1

Consider Alternative Diagnoses

Lyme disease must be excluded if the patient is in an endemic area, as cephalexin is completely ineffective for Lyme disease and should never be used when erythema migrans cannot be reliably distinguished from cellulitis. 2 In Lyme-endemic regions during summer months, use cefuroxime axetil or amoxicillin-clavulanate instead, which cover both cellulitis and early Lyme disease. 2

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, which hastens clinical improvement. 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 underlying venous insufficiency, lymphedema, and chronic edema as part of routine care, as these predispose to treatment failure and recurrence. 1

Treatment Duration After Switching

Treat for 5 days if clinical improvement occurs with the new regimen; extend only if symptoms have not improved within this timeframe. 1, 4 Reassess in 48-72 hours to verify clinical response, as treatment failure rates of 21% have been reported with some oral regimens. 1

Why Adding MRSA Coverage to Cephalexin is Wrong

Do not simply add TMP-SMX to the existing cephalexin regimen. A landmark randomized controlled trial of 500 patients demonstrated that cephalexin plus TMP-SMX was no more effective than cephalexin alone for uncomplicated cellulitis (83.5% vs 85.5% cure rate, p=0.50). 5, 6 This combination provides no additional benefit in pure cellulitis without abscess, ulcer, or purulent drainage. 1

Common Pitfall to Avoid

Do not continue ineffective antibiotics beyond 48-72 hours, as progression despite appropriate therapy indicates either resistant organisms or a deeper/different infection than initially recognized. 1 Your patient has already received 14 days of cephalexin—continuing this regimen or simply adding to it represents a fundamental treatment error.