What is the appropriate antibiotic regimen for an otherwise healthy adult with uncomplicated lower extremity cellulitis?

Antibiotic Selection for Uncomplicated Lower Extremity Cellulitis in Healthy Adults

For an otherwise healthy adult with uncomplicated lower extremity cellulitis, prescribe cephalexin 500 mg orally every 6 hours or dicloxacillin 250–500 mg orally every 6 hours for exactly 5 days, extending only if warmth, tenderness, or erythema have not improved. 1

First-Line Beta-Lactam Monotherapy

• Beta-lactam monotherapy is the standard of care for typical uncomplicated cellulitis, achieving 96% clinical success because the primary pathogens are beta-hemolytic streptococci (especially Streptococcus pyogenes) and methicillin-sensitive Staphylococcus aureus. 1, 2, 3

• Recommended 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

• For hospitalized patients requiring IV therapy, cefazolin 1–2 g IV every 8 hours is the preferred beta-lactam. 1

Treatment Duration: 5 Days Is Sufficient

• Treat for exactly 5 days if clinical improvement occurs (resolution of warmth/tenderness, improving erythema, no fever); extend only if symptoms have not improved. 1

• High-quality randomized controlled trial evidence demonstrates that 5-day courses are as effective as 10-day courses for uncomplicated cellulitis, with 98% clinical resolution at 14 days and 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 (and When NOT To)

• MRSA is an uncommon cause of typical nonpurulent cellulitis even in high-prevalence settings, so routine MRSA coverage is unnecessary. 1, 2, 3

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

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

• When MRSA coverage is indicated, use: 1

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

Hospitalization Criteria

• Admit patients with lower extremity cellulitis when any of the following are present: 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" tissue, gas or bullae)
  • Severe immunocompromise or neutropenia
  • Failure of outpatient therapy after 24–48 hours

• For severe cellulitis with systemic toxicity, use vancomycin 15–20 mg/kg IV every 8–12 hours PLUS piperacillin-tazobactam 3.375–4.5 g IV every 6 hours. 1

Essential Adjunctive Measures

• Elevate the affected leg 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, 4

Common Pitfalls to Avoid

• Do not add MRSA coverage routinely for typical nonpurulent cellulitis without the specific risk factors listed above—this overtreats 96% of cases and drives antimicrobial resistance. 1

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

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

• Do not obtain blood cultures for typical uncomplicated cellulitis—they are positive in only ~5% of cases and represent unnecessary resource utilization. 1

Monitoring and Follow-Up

• Reassess patients within 24–48 hours to confirm clinical improvement—treatment failure rates of approximately 21% have been reported with some oral regimens. 1

• If no improvement after 48–72 hours of appropriate beta-lactam therapy, consider: 1

  • Resistant organisms (MRSA)
  • Undrained abscess (obtain ultrasound if clinical uncertainty exists)
  • Deeper infection (necrotizing fasciitis, septic arthritis, osteomyelitis)
  • Alternative diagnoses (deep vein thrombosis, venous stasis dermatitis, contact dermatitis)