What is the first‑line oral antibiotic for uncomplicated cellulitis in an adult without known drug allergies or risk factors for methicillin‑resistant Staphylococcus aureus (MRSA)?

First-Line Oral Antibiotic for Uncomplicated Cellulitis

For an adult with uncomplicated cellulitis and no MRSA risk factors, prescribe cephalexin 500 mg orally every 6 hours for 5 days. 1

Why Beta-Lactam Monotherapy Is Standard

Beta-lactam monotherapy achieves 96% clinical success in typical nonpurulent cellulitis because the primary pathogens are beta-hemolytic streptococci (especially Streptococcus pyogenes) and methicillin-sensitive Staphylococcus aureus 1. MRSA is an uncommon cause of typical cellulitis even in high-prevalence settings, making routine MRSA coverage unnecessary and potentially overtreatment 1.

Recommended Oral Beta-Lactam Options

• Cephalexin 500 mg orally every 6 hours 1, 2, 3
• Dicloxacillin 250–500 mg orally every 6 hours 1, 2, 3
• Amoxicillin (dose not specified but listed as appropriate) 1
• Penicillin V 250–500 mg orally four times daily 1

All of these agents provide excellent coverage against the typical pathogens and are equally effective 1.

Treatment Duration: 5 Days Is Sufficient

Treat for exactly 5 days if clinical improvement occurs (resolution of warmth and tenderness, improving erythema, absence of fever); extend only if symptoms have not improved within this timeframe 1. High-quality randomized controlled trial evidence demonstrates that 5-day courses are as effective as 10-day courses for uncomplicated cellulitis 1. Traditional 7–14-day regimens are no longer necessary 1.

When to Add MRSA Coverage (and When NOT To)

Do NOT add MRSA coverage for typical nonpurulent cellulitis without specific risk factors 1. Adding MRSA coverage to beta-lactam therapy provides no additional benefit in typical cases 1.

Add MRSA-active antibiotics ONLY when any of the following risk factors are present: 1

• Penetrating trauma or injection drug use
• Purulent drainage or exudate visible at the infection site
• Known MRSA colonization or prior MRSA infection
• Systemic inflammatory response syndrome (fever >38°C, tachycardia >90 bpm, tachypnea >24 breaths/min)
• Failure to respond to beta-lactam therapy after 48–72 hours

MRSA-Active Regimens When Risk Factors Are Present

If MRSA coverage is needed, choose one of these options: 1

• Clindamycin 300–450 mg orally every 6 hours as single-agent therapy (covers both streptococci and MRSA), but use only if local MRSA clindamycin resistance is <10% 1, 4
• Trimethoprim-sulfamethoxazole 1–2 double-strength tablets twice daily PLUS a beta-lactam (cephalexin or amoxicillin) 1
• Doxycycline 100 mg orally twice daily PLUS a beta-lactam 1

Critical pitfall: Never use doxycycline or trimethoprim-sulfamethoxazole as monotherapy for typical cellulitis because they lack reliable activity against beta-hemolytic streptococci 1.

Penicillin Allergy Management

For patients with non-immediate penicillin allergy (no urticaria, angioedema, bronchospasm, or anaphylaxis), cephalexin remains acceptable because cross-reactivity is only 2–4% 1, 2. However, avoid cephalexin in patients with confirmed immediate-type amoxicillin allergy due to identical R1 side chains 1.

For true penicillin-allergic patients, use clindamycin 300–450 mg orally every 6 hours (if local MRSA clindamycin resistance <10%) 1.

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 1
• Examine interdigital toe spaces for tinea pedis, fissuring, scaling, or maceration; treating these eradicates colonization and reduces recurrent infection 1
• Address predisposing conditions including venous insufficiency, lymphedema, chronic edema, obesity, and eczema 1

Hospitalization Criteria

Hospitalize patients with any of the following: 1

• Systemic inflammatory response syndrome (fever, tachycardia, hypotension, altered mental status)
• Signs of deeper or necrotizing infection (severe pain out of proportion to examination, skin anesthesia, rapid progression, "wooden-hard" subcutaneous tissues)
• Severe immunocompromise or neutropenia
• Failure of outpatient treatment after 24–48 hours

Common Pitfalls to Avoid

• Do not reflexively add MRSA coverage to all cellulitis cases; this represents overtreatment in ~96% of typical cases and promotes antimicrobial resistance 1
• Do not automatically extend therapy to 7–10 days based on residual erythema alone; some inflammation persists even after bacterial eradication 1
• Do not use combination therapy (trimethoprim-sulfamethoxazole plus cephalexin) for pure cellulitis without abscess, ulcer, or purulent drainage, as it is no more efficacious than cephalexin alone 1
• Reassess within 24–48 hours to verify clinical response, as treatment failure rates of 21% have been reported with some oral regimens 1