What is the appropriate first‑line antibiotic for uncomplicated cellulitis in a patient without a penicillin allergy?

Antibiotic Selection for Cellulitis Without Penicillin Allergy

For uncomplicated cellulitis presenting with erythema, warmth, and streaking in a patient without penicillin allergy, cloxacillin (or its equivalent dicloxacillin) is the most appropriate first-line choice among the options provided, as it delivers targeted anti-staphylococcal and anti-streptococcal coverage that aligns with guideline-recommended beta-lactam monotherapy. 1

First-Line Beta-Lactam Monotherapy

• Beta-lactam monotherapy is the standard of care for typical uncomplicated cellulitis, achieving 96% clinical success because MRSA is an uncommon cause even in high-prevalence settings. 1

• The Infectious Diseases Society of America explicitly recommends penicillinase-resistant semisynthetic penicillins (dicloxacillin/cloxacillin) or first-generation cephalosporins (cephalexin) as first-line agents for cellulitis, providing Grade A-I evidence. 1, 2

• Cloxacillin 250–500 mg orally every 6 hours for 5 days provides excellent coverage against beta-hemolytic streptococci (especially Streptococcus pyogenes) and methicillin-sensitive Staphylococcus aureus, the primary pathogens in 85% of culturable cases. 1, 3, 4

Why the Other Options Are Inappropriate

Erythromycin (Option B)

• Erythromycin is considered a second-line agent and should be reserved for patients with true penicillin allergy or specific contraindications to beta-lactams. 5
• While macrolides show similar efficacy to beta-lactams in meta-analyses, guideline societies prioritize beta-lactams as first-line to minimize resistance and preserve macrolide effectiveness. 1, 5

Penicillin (Option C)

• Plain penicillin V lacks adequate anti-staphylococcal activity because it is destroyed by beta-lactamases produced by Staphylococcus aureus, which accounts for a significant proportion of cellulitis cases. 1, 4
• Penicillin V is appropriate only when streptococcal infection is certain, but cellulitis requires empiric coverage for both streptococci and staphylococci. 1

Tetracycline/Doxycycline (Option D)

• Tetracyclines must never be used as monotherapy for typical cellulitis because they lack reliable activity against beta-hemolytic streptococci, the most common pathogen. 1
• Doxycycline requires combination with a beta-lactam when MRSA coverage is needed, but MRSA coverage is unnecessary for typical nonpurulent cellulitis without specific risk factors (penetrating trauma, purulent drainage, injection drug use, known MRSA colonization, or systemic inflammatory response syndrome). 1

Treatment Duration and Monitoring

• Treat for exactly 5 days if clinical improvement occurs (resolution of warmth, tenderness, and progressive reduction in erythema); extend only if symptoms have not improved within this timeframe. 1, 6
• High-quality randomized controlled trial evidence confirms that 5-day courses are as effective as 10-day courses for uncomplicated cellulitis, eliminating the need for traditional 7–14-day regimens. 1, 6
• Reassess within 24–48 hours to verify clinical response; treatment failure should prompt consideration of resistant organisms, cellulitis mimickers (venous stasis dermatitis, DVT), or deeper infection. 1, 4

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; treating these conditions eradicates colonization and reduces recurrent infection risk. 1
• Address predisposing conditions including venous insufficiency, lymphedema, chronic edema, eczema, and obesity to minimize recurrence. 1, 3

When to Add MRSA Coverage (Not Needed in This Case)

MRSA-active antibiotics should be added only when specific risk factors are present:

• Penetrating trauma or injection drug use 1
• Purulent drainage or exudate 1
• Evidence of MRSA infection elsewhere or known nasal colonization 1
• Systemic inflammatory response syndrome (fever >38°C, tachycardia >90 bpm, hypotension, altered mental status) 1
• Failure to respond to beta-lactam therapy after 48–72 hours 1

In the absence of these factors, adding MRSA coverage represents overtreatment and increases antibiotic resistance without improving outcomes. 1, 4

Critical Pitfall to Avoid

Do not reflexively add MRSA coverage for typical cellulitis simply because the patient appears ill or has prominent streaking; beta-lactam monotherapy achieves 96% success in appropriately selected patients, and MRSA is an uncommon cause of typical nonpurulent cellulitis even in high-prevalence settings. 1, 3, 4