What is the recommended antibiotic regimen for a patient with cellulitis who is allergic to amoxicillin (amoxicillin)?

Antibiotic Management for Cellulitis with Amoxicillin Allergy

Recommended Antibiotic Regimen

For a patient with uncomplicated cellulitis and amoxicillin allergy, use cephalexin 500 mg orally four times daily for 5 days, or alternatively clindamycin 300-450 mg orally three times daily for 5 days if local MRSA resistance is <10%. 1

Treatment Algorithm Based on Clinical Presentation

For Typical Nonpurulent Cellulitis (Most Common)

First-line alternatives to amoxicillin:

• Cephalexin 500 mg orally four times daily for 5 days 1
• Dicloxacillin 250-500 mg orally every 6 hours for 5 days 1
• Clindamycin 300-450 mg orally three times daily for 5 days (provides both streptococcal and MRSA coverage) 1

The Infectious Diseases Society of America confirms that beta-lactam monotherapy (including cephalosporins like cephalexin) is successful in 96% of typical cellulitis cases, and MRSA coverage is unnecessary for nonpurulent cellulitis without specific risk factors 1. Extend treatment beyond 5 days only if clinical improvement has not occurred within this timeframe. 1

Important Caveat About Cephalosporin Use

If the amoxicillin allergy is a true IgE-mediated reaction (anaphylaxis, angioedema, urticaria), avoid cephalexin and dicloxacillin due to cross-reactivity risk. In this scenario, clindamycin 300-450 mg orally three times daily becomes the preferred agent as it avoids beta-lactam cross-reactivity entirely while providing excellent streptococcal coverage. 1

For Purulent Cellulitis or MRSA Risk Factors

Add MRSA coverage when these specific features are present:

• Penetrating trauma or injection drug use 1
• Purulent drainage or exudate 1
• Known MRSA colonization or documented MRSA infection elsewhere 1
• Systemic inflammatory response syndrome (SIRS) 1

Recommended regimens for MRSA coverage:

• Clindamycin monotherapy 300-450 mg orally three times daily for 5 days (covers both streptococci and MRSA) 1
• Trimethoprim-sulfamethoxazole (TMP-SMX) 1-2 double-strength tablets twice daily PLUS a beta-lactam (if no true allergy) for 5 days 1
• Doxycycline 100 mg orally twice daily PLUS a beta-lactam (if no true allergy) for 5 days 1

Critical pitfall: Never use TMP-SMX or doxycycline as monotherapy for typical cellulitis, as they lack reliable activity against beta-hemolytic streptococci, which are the primary pathogens. 1 Clindamycin is the only oral agent that can be used alone when MRSA coverage is needed. 1

For Severe Cellulitis Requiring Hospitalization

If systemic toxicity, rapid progression, or suspected necrotizing fasciitis:

• Vancomycin 15-20 mg/kg IV every 8-12 hours PLUS piperacillin-tazobactam 3.375-4.5 g IV every 6 hours 1
• Alternative: Linezolid 600 mg IV twice daily PLUS piperacillin-tazobactam 1
• Duration: 7-14 days for severe infections, guided by clinical response 1

Dosing Duration Evidence

The Infectious Diseases Society of America establishes 5 days as the standard treatment duration for uncomplicated cellulitis when clinical improvement occurs, with extension only if symptoms persist. 1 This represents a significant departure from traditional 7-14 day courses and is supported by high-quality evidence. 1

Adjunctive Measures

• Elevate the affected extremity to promote drainage and hasten improvement 1
• Treat predisposing conditions including tinea pedis, toe web abnormalities, venous insufficiency, and lymphedema 1
• Consider systemic corticosteroids (prednisone 40 mg daily for 7 days) in non-diabetic adults, though evidence is limited 1

Key Clinical Decision Points

Reassess at 24-48 hours to verify clinical response, as treatment failure rates can reach 21% with some regimens. 1 If cellulitis is spreading despite appropriate antibiotics, immediately evaluate for necrotizing fasciitis (severe pain out of proportion to exam, skin anesthesia, rapid progression, systemic toxicity) and obtain emergent surgical consultation if suspected. 1

Do not reflexively add MRSA coverage simply because MRSA prevalence is high in your area—beta-lactam monotherapy remains appropriate for typical nonpurulent cellulitis even in high-MRSA settings. 1, 2 The randomized controlled trial by Pallin et al. demonstrated that adding TMP-SMX to cephalexin provided no benefit in uncomplicated cellulitis (85% vs 82% cure rate, p=0.66). 3