What are the best oral antibiotics for an adult patient with uncomplicated cellulitis?

Best Oral Antibiotics for Uncomplicated Cellulitis

For typical uncomplicated cellulitis in adults, cephalexin 500 mg orally four times daily for 5 days is the preferred first-line treatment, with beta-lactam monotherapy achieving 96% success rates. 1

First-Line Beta-Lactam Monotherapy

Beta-lactam antibiotics remain the standard of care because MRSA is an uncommon cause of typical cellulitis, even in high-prevalence settings. 1 The evidence is unequivocal: beta-lactam treatment succeeds in 96% of patients, confirming that MRSA coverage is usually unnecessary. 1

Recommended oral beta-lactam options include: 1

• Cephalexin 500 mg orally every 6 hours (most commonly prescribed)
• Dicloxacillin 250-500 mg every 6 hours
• Amoxicillin (dose varies by severity)
• Amoxicillin-clavulanate 875/125 mg twice daily
• Penicillin V 250-500 mg four times daily

These agents provide excellent coverage against beta-hemolytic streptococci (especially Streptococcus pyogenes) and methicillin-sensitive Staphylococcus aureus, which are the primary pathogens in nonpurulent cellulitis. 1, 2

Treatment Duration: The 5-Day Rule

Treat for exactly 5 days if clinical improvement has occurred. 1 Extend treatment only if symptoms have not improved within this timeframe. 1 Traditional 7-14 day courses are no longer necessary for uncomplicated cases. 1 This represents a major shift from historical practice and is supported by high-quality randomized controlled trial evidence. 1

Stop antibiotics after 5 days if: 1

• Warmth and tenderness have resolved
• Erythema is improving
• Patient is afebrile

When MRSA Coverage Is Actually Needed

Do NOT add MRSA coverage reflexively. 1 Adding MRSA coverage to beta-lactam therapy provides no additional benefit in typical cases. 1 A landmark randomized controlled trial demonstrated that combination therapy with trimethoprim-sulfamethoxazole plus cephalexin is no more efficacious than cephalexin alone in pure cellulitis without abscess, ulcer, or purulent drainage. 1, 3

Add MRSA coverage ONLY when these specific risk factors are present: 1

• Penetrating trauma or injection drug use
• Purulent drainage or exudate visible
• Evidence of MRSA infection elsewhere or nasal MRSA colonization
• Systemic inflammatory response syndrome (SIRS)

When MRSA coverage is genuinely indicated, use: 1

• Clindamycin 300-450 mg orally every 6 hours (provides single-agent coverage for both streptococci and MRSA, avoiding need for combination therapy)
• Trimethoprim-sulfamethoxazole 1-2 double-strength tablets twice daily PLUS a beta-lactam
• Doxycycline 100 mg orally twice daily PLUS a beta-lactam

Critical Pitfalls to Avoid

Never use doxycycline or trimethoprim-sulfamethoxazole as monotherapy for typical cellulitis. 1 These agents lack reliable activity against beta-hemolytic streptococci and will result in treatment failure. 1 Doxycycline must be combined with a beta-lactam when treating typical nonpurulent cellulitis. 1

Do not extend treatment to 10-14 days based on residual erythema alone. 1 Some inflammation persists even after bacterial eradication, and extending treatment based on tradition rather than evidence increases antibiotic resistance without improving outcomes. 1

Do not combine multiple antibiotics when monotherapy is appropriate. 1 This increases adverse effects without improving outcomes and represents overtreatment. 1

Special Populations and Scenarios

Penicillin/Cephalosporin Allergy

For patients with beta-lactam allergies, clindamycin 300-450 mg orally every 6 hours for 5 days is the optimal choice, providing single-agent coverage for both streptococci and MRSA. 1 Use clindamycin only if local MRSA clindamycin resistance rates are <10%. 1

Alternative options include fluoroquinolones (levofloxacin 500 mg daily), though these should be reserved for patients with beta-lactam allergies and lack adequate MRSA coverage. 1

Bite-Associated Cellulitis

Amoxicillin-clavulanate 875/125 mg twice daily is the preferred agent for cellulitis associated with human or animal bites, providing single-agent coverage for both streptococci and polymicrobial oral flora. 1

Pediatric Cellulitis

For children with nonpurulent cellulitis, cephalexin 25-50 mg/kg/day divided 4 times daily for 5 days is first-line treatment. 4 For purulent cellulitis or MRSA risk factors, consider empiric CA-MRSA coverage. 4

Essential Adjunctive Measures

Elevation of the affected extremity hastens improvement by promoting gravity drainage of edema and inflammatory substances. 1 This simple intervention is often neglected but critical for optimal outcomes. 1

Treat predisposing conditions: 1

• Examine interdigital toe spaces for tinea pedis, fissuring, scaling, or maceration
• Address venous insufficiency and lymphedema with compression stockings once acute infection resolves
• Manage chronic edema, obesity, and eczema

These measures reduce recurrence risk, which ranges from 8-20% annually in patients with previous leg cellulitis. 1