What is the appropriate first‑line oral antibiotic for an adult with uncomplicated bacterial skin infection such as cellulitis, impetigo, or folliculitis, and what alternatives are recommended for purulent infections, suspected community‑associated methicillin‑resistant Staphylococcus aureus, penicillin allergy, or severe infection requiring intravenous therapy?

First-Line Oral Antibiotic for Uncomplicated Bacterial Skin Infections

For uncomplicated non-purulent cellulitis, impetigo, or folliculitis in adults, prescribe cephalexin 500 mg orally every 6 hours or dicloxacillin 250–500 mg orally every 6 hours for exactly 5 days; extend only if warmth, tenderness, or erythema have not improved. 1

Standard Beta-Lactam Monotherapy

• Beta-lactam monotherapy achieves approximately 96% clinical success in typical non-purulent skin infections because the primary pathogens are beta-hemolytic streptococci (especially Streptococcus pyogenes) and methicillin-sensitive Staphylococcus aureus. 1

• Recommended first-line oral agents include:

  • Cephalexin 500 mg every 6 hours 1
  • Dicloxacillin 250–500 mg every 6 hours 1
  • Amoxicillin 500 mg three times daily 1
  • Penicillin V 250–500 mg four times daily 1

• All of these agents provide excellent streptococcal and MSSA coverage and are equally effective for uncomplicated infections. 1

Treatment Duration: The 5-Day Rule

• Treat for exactly 5 days if clinical improvement occurs (resolution of warmth/tenderness, improving erythema, no fever); extend only if symptoms persist. 1

• High-quality randomized controlled trial evidence demonstrates that 5-day courses are as effective as 10-day courses, achieving 98% clinical resolution at 14 days with no relapses by 28 days. 1

• Traditional 7–14-day regimens are unnecessary for uncomplicated cases and promote antimicrobial resistance without improving outcomes. 1

When to Add MRSA Coverage (Purulent Infections)

Add MRSA-active antibiotics only when specific risk factors are present:

• Penetrating trauma or injection drug use 1
• Visible purulent drainage or exudate at the infection site 1
• Known MRSA colonization or prior MRSA infection 1
• Systemic inflammatory response syndrome (fever >38°C, heart rate >90 bpm, respiratory rate >24 breaths/min) 1
• Failure to respond to beta-lactam therapy after 48–72 hours 1

MRSA is an uncommon cause of typical non-purulent cellulitis even in high-prevalence settings, making routine MRSA coverage unnecessary and potentially harmful. 1

Oral MRSA-Active Regimens (5 days)

• Clindamycin 300–450 mg orally every 6 hours provides single-agent coverage for both streptococci and MRSA, but use only if local MRSA clindamycin resistance is <10%. 1

• Trimethoprim-sulfamethoxazole 1–2 double-strength tablets twice daily PLUS a beta-lactam (cephalexin or amoxicillin) ensures coverage of both MRSA and streptococci. 1

• Doxycycline 100 mg orally twice daily PLUS a beta-lactam is appropriate for adults; doxycycline is contraindicated in children <8 years and pregnant women. 1

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 non-immediate penicillin allergy, cephalexin remains acceptable because cross-reactivity is only 2–4%; avoid cephalexin in 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

• Alternative for severe penicillin allergy: levofloxacin 500 mg daily for 5 days, though fluoroquinolones should be reserved for patients with beta-lactam allergies to minimize resistance. 1

Severe Infections Requiring Intravenous Therapy

Hospitalize patients with any of the following:

• Systemic inflammatory response syndrome (fever, tachycardia, hypotension, altered mental status) 1
• Signs of deeper or necrotizing infection (severe pain out of proportion, skin anesthesia, rapid progression, "wooden-hard" tissue) 1
• Severe immunocompromise or neutropenia 1
• Failure of outpatient therapy after 24–48 hours 1

Intravenous Antibiotic Regimens

• For uncomplicated cellulitis requiring hospitalization without MRSA risk factors: cefazolin 1–2 g IV every 8 hours or nafcillin 2 g IV every 6 hours. 1

• For severe cellulitis with systemic toxicity 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 IV MRSA-active agents (A-I evidence):

  • Linezolid 600 mg IV twice daily 1, 2
  • Daptomycin 4 mg/kg IV once daily 1
  • Clindamycin 600 mg IV every 8 hours (only if local resistance <10%) 1

• Duration for complicated infections is 7–14 days, individualized based on clinical response. 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 and treat these conditions to eradicate colonization and reduce recurrent infection. 1

• Address predisposing conditions including venous insufficiency, lymphedema, chronic edema, obesity, and eczema to lower recurrence risk. 1

Critical Pitfalls to Avoid

• Do not add MRSA coverage routinely for typical non-purulent cellulitis without the specified risk factors; this overtreats approximately 96% of cases and promotes resistance. 1

• Do not automatically extend therapy to 7–10 days based solely on residual erythema; extend only if warmth, tenderness, or erythema have not improved after 5 days. 1

• Do not use doxycycline or trimethoprim-sulfamethoxazole as monotherapy for typical cellulitis, as they lack reliable activity against beta-hemolytic streptococci, the predominant pathogens. 1

• Do not delay surgical consultation if signs of necrotizing infection, deep abscess, or systemic toxicity develop; timely debridement is critical. 1

• Do not treat simple abscesses with antibiotics alone; incision and drainage is the primary treatment, with antibiotics serving only an adjunctive role when specific risk factors are present. 1

Monitoring and Follow-Up

• Reassess patients within 24–48 hours to confirm clinical response; oral regimens have reported failure rates around 21% if no response is seen. 1

• If no improvement after 48–72 hours of appropriate therapy, consider resistant organisms (MRSA), undrained abscess, deeper infection (necrotizing fasciitis, osteomyelitis), or alternative diagnoses. 1