What is the best antibiotic treatment for a patient in their late 50s with cellulitis of the right lower extremity who is currently taking Skyrizi (risankizumab)?

Antibiotic Treatment for Cellulitis in a Patient on Skyrizi

Direct Recommendation

For this patient with uncomplicated lower extremity cellulitis on Skyrizi (risankizumab), start cephalexin 500 mg orally every 6 hours for 5 days, extending only if clinical improvement has not occurred within this timeframe. 1, 2

Rationale for Beta-Lactam Monotherapy

• Beta-lactam monotherapy is the standard of care for typical uncomplicated cellulitis and is successful in 96% of patients, even in settings with high MRSA prevalence. 1, 2

• The Infectious Diseases Society of America provides Grade A-I evidence that first-generation cephalosporins (e.g., cephalexin) are effective for treating cellulitis, targeting the primary pathogens: β-hemolytic streptococci and methicillin-sensitive S. aureus. 1, 3

• MRSA is an uncommon cause of typical nonpurulent cellulitis and routine coverage is unnecessary, even in immunosuppressed patients on biologics like Skyrizi. 1, 2

Immunosuppression Considerations with Skyrizi

• While Skyrizi (risankizumab) is an IL-23 inhibitor that causes immunosuppression, this does not automatically warrant MRSA coverage for typical cellulitis. 1, 2

• The standard 5-day treatment duration applies unless clinical improvement has not occurred, at which point extension or reassessment is warranted. 1, 2

• Severe immunocompromise requiring hospitalization would include neutropenia or systemic signs of toxicity (fever, hypotension, altered mental status), not simply biologic therapy alone. 1, 2

When to Add MRSA Coverage

Add MRSA-active antibiotics ONLY if specific risk factors are present: 1, 2

• Penetrating trauma or injection drug use
• Purulent drainage or exudate visible on examination
• Evidence of MRSA infection elsewhere or known nasal colonization
• Systemic inflammatory response syndrome (SIRS): fever >38°C, tachycardia >90, hypotension, or altered mental status
• Failure to respond to beta-lactam therapy after 48-72 hours

If MRSA coverage is needed, use: 1, 2

• Clindamycin 300-450 mg orally three times daily (covers both streptococci and MRSA as monotherapy), OR
• Trimethoprim-sulfamethoxazole 1-2 DS tablets twice daily PLUS cephalexin (combination required as TMP-SMX lacks streptococcal coverage), OR
• Doxycycline 100 mg twice daily PLUS cephalexin (combination required as doxycycline has unreliable streptococcal activity)

Alternative First-Line Options

If cephalexin is unavailable or not tolerated: 1, 2

• Dicloxacillin 250-500 mg orally every 6 hours
• Amoxicillin-clavulanate 875/125 mg twice daily (provides broader coverage but not necessary for typical cellulitis)
• Penicillin or amoxicillin alone (adequate streptococcal coverage)

Critical Adjunctive Measures

• Elevate the affected extremity to promote gravity drainage of edema and inflammatory substances. 1, 2

• Examine interdigital toe spaces carefully for tinea pedis, fissuring, scaling, or maceration, and treat if present to prevent recurrence. 1, 2

• Treat predisposing conditions such as venous insufficiency, lymphedema, eczema, or obesity. 1, 2

Reassessment and Treatment Failure

• Reassess within 24-48 hours to ensure clinical improvement (reduction in erythema, warmth, swelling, pain). 1, 2

• If no improvement or worsening occurs, consider: 1, 2

  • Adding MRSA coverage (switch to clindamycin or add TMP-SMX to cephalexin)
  • Evaluating for abscess with ultrasound (requires incision and drainage)
  • Assessing for necrotizing fasciitis (severe pain out of proportion, skin anesthesia, rapid progression, gas in tissue, bullous changes—requires emergent surgical consultation)
  • Considering cellulitis mimickers (venous stasis dermatitis, contact dermatitis, DVT)

Hospitalization Criteria

Admit if any of the following are present: 1, 2

• SIRS criteria (fever, tachycardia, hypotension, altered mental status)
• Concern for deeper or necrotizing infection
• Severe immunocompromise with systemic signs (not simply being on Skyrizi)
• Failure of outpatient treatment after 24-48 hours
• Poor adherence anticipated

Common Pitfalls to Avoid

• Do not routinely add MRSA coverage for typical nonpurulent cellulitis simply because the patient is on immunosuppressive therapy—reserve MRSA-active agents for specific high-risk scenarios. 1, 2

• Do not use TMP-SMX or doxycycline as monotherapy for typical cellulitis, as their activity against β-hemolytic streptococci is unreliable. 1, 2

• Do not automatically extend treatment to 10 days—5 days is as effective as 10 days for uncomplicated cellulitis if clinical improvement occurs. 1, 2

• Do not use broad-spectrum antibiotics (e.g., amoxicillin-clavulanate, ceftriaxone, piperacillin-tazobactam) for uncomplicated cellulitis, as narrow-spectrum agents are equally effective and reduce antibiotic resistance. 1, 4