What is the first‑line antibiotic regimen for a typical adult with a bacterial skin infection and no known drug allergies?

First-Line Antibiotic for Bacterial Skin Infections in Adults

For a typical adult with a bacterial skin infection and no drug allergies, cephalexin 500 mg orally four times daily for 5 days is the preferred first-line antibiotic, providing excellent coverage against streptococci and methicillin-sensitive Staphylococcus aureus (MSSA) with 97% resistance-free susceptibility. 1

Treatment Algorithm Based on Clinical Presentation

For Non-Purulent Cellulitis (Most Common Scenario)

• Start with beta-lactam monotherapy targeting streptococci, as these organisms cause the majority of typical cellulitis cases 2
• Cephalexin 500 mg orally four times daily (or 250 mg four times daily for mild infections) achieves 96% clinical success in typical cellulitis 1
• Alternative beta-lactam options with equivalent efficacy include:
  • Dicloxacillin 250-500 mg four times daily 1
  • Penicillin VK 250-500 mg every 6 hours for confirmed streptococcal infections 2
  • Amoxicillin-clavulanate 875/125 mg twice daily (broader coverage but not routinely necessary) 1

When to Add MRSA Coverage

Do not reflexively add MRSA coverage unless specific risk factors are present 1. Add MRSA-active antibiotics only if:

• Purulent drainage or exudate is present 2, 1
• History of penetrating trauma or injection drug use 2, 1
• Known MRSA colonization or previous MRSA infection 2, 1
• Failure to respond to initial beta-lactam therapy after 48 hours 1
• Systemic inflammatory response syndrome (SIRS) is present 2

If MRSA coverage is needed, use clindamycin 300-450 mg orally four times daily as monotherapy, which covers both streptococci and MRSA, eliminating the need for combination therapy 2, 1

Treatment Duration and Monitoring

• Standard duration is 5 days if clinical improvement occurs 1
• Mandatory reassessment at 48 hours to verify clinical response, as treatment failure rates of 21% have been reported with some oral regimens 1
• Extend treatment only if symptoms have not improved within the initial 5-day timeframe 1

Critical Pitfalls to Avoid

• Do not use doxycycline as monotherapy for typical cellulitis, as its activity against beta-hemolytic streptococci is unreliable 1
• Do not use trimethoprim-sulfamethoxazole alone for typical cellulitis, as it has poor activity against streptococci 2, 1
• Avoid combination therapy with ampicillin and cloxacillin for routine skin infections, except for cellulitis and infected eczemas 3
• Do not add MRSA coverage simply because the patient is hospitalized—MRSA is an uncommon cause of typical cellulitis even in high-prevalence settings 1

Resistance Patterns to Consider

• S. aureus demonstrates 89.5% resistance to penicillin and ampicillin, making these poor choices 3
• S. aureus remains 93% sensitive to cloxacillin, cephalexin, and cotrimoxazole 3
• Erythromycin resistance in S. aureus is 18.7%, making it a less preferred alternative 3
• Methicillin-resistant S. aureus accounts for only 4.2% of total organisms isolated in primary pyodermas 3

Adjunctive Measures

• Elevation of the affected extremity hastens improvement by promoting gravitational drainage 1
• Examine interdigital toe spaces for tinea pedis, as treating predisposing conditions reduces recurrent infection risk 1
• Address underlying venous insufficiency, lymphedema, and chronic edema 1

When to Escalate to Parenteral Therapy

Hospitalization with IV antibiotics is indicated if:

• Systemic inflammatory response syndrome is present 1
• Hypotension or hemodynamic instability occurs 1
• Altered mental status or confusion develops 1
• Severe immunocompromise or concern for necrotizing infection exists 1

For hospitalized patients requiring IV therapy, vancomycin 15-20 mg/kg IV every 8-12 hours is first-line 1, or nafcillin 1-2 g IV every 4-6 hours for MSSA infections 2