What is the first-line therapy for uncomplicated cellulitis of the lower extremity?

First-Line Therapy for Uncomplicated Cellulitis of the Lower Extremity

For uncomplicated cellulitis of the lower extremity, initiate oral therapy with either cephalexin 500 mg every 6 hours or dicloxacillin 250-500 mg every 6 hours for 5 days, targeting β-hemolytic streptococci and methicillin-sensitive Staphylococcus aureus. 1, 2

Antibiotic Selection Algorithm

Standard First-Line Options (No MRSA Risk Factors)

• Cephalexin 500 mg every 6 hours is the preferred first-generation cephalosporin, providing effective coverage against streptococci and methicillin-sensitive S. aureus 1, 2, 3
• Dicloxacillin 250 mg every 6 hours (mild-moderate) or 500 mg every 6 hours (severe) is an equally effective penicillinase-resistant penicillin alternative 1, 4
• Amoxicillin-clavulanate provides broader coverage including β-lactamase-producing organisms and is appropriate for first-line therapy 2, 5
• Penicillin VK or amoxicillin can be used when streptococcal infection is strongly suspected 1, 5

Penicillin Allergy Alternatives

• Clindamycin 300-450 mg three times daily is the preferred option for penicillin-allergic patients, as 99.5% of S. pyogenes strains remain susceptible 2, 6
• Macrolides (erythromycin) should be used cautiously due to regional resistance among group A streptococci in the United States 1

When to Add MRSA Coverage

Do NOT routinely cover MRSA for typical cellulitis. 1, 2 MRSA is an unusual cause of non-purulent cellulitis and empiric coverage is unnecessary unless specific risk factors are present 7, 8

Add MRSA coverage ONLY when these risk factors exist: 1, 2

• Penetrating trauma or injection drug use
• Purulent drainage or exudate visible
• Evidence of MRSA infection at another site or known nasal colonization
• Systemic inflammatory response syndrome (SIRS): fever, tachycardia, hypotension, altered mental status
• Failure to respond to β-lactam therapy after 48-72 hours

MRSA coverage options when indicated: 1, 2

• Clindamycin alone (covers both streptococci and MRSA)
• Trimethoprim-sulfamethoxazole (TMP-SMX) 1-2 DS tablets twice daily PLUS a β-lactam (cephalexin, penicillin, or amoxicillin) - never use TMP-SMX as monotherapy due to inadequate streptococcal coverage 2
• Doxycycline 100 mg twice daily PLUS a β-lactam 2

Treatment Duration

• 5 days of antibiotic therapy is as effective as 10 days for uncomplicated cellulitis 1, 9
• Extend treatment beyond 5 days ONLY if the infection has not improved within this timeframe 1, 2
• Reassess within 24-48 hours for outpatients to ensure clinical improvement 2

Essential Adjunctive Measures

These non-pharmacologic interventions are critical and often neglected:

• Elevate the affected extremity to promote gravity drainage of edema and inflammatory substances 1
• Carefully examine interdigital toe spaces for tinea pedis, fissuring, scaling, or maceration - treating these eradicates pathogen colonization and reduces recurrence 1, 2
• Treat predisposing conditions including venous insufficiency, lymphedema, eczema, obesity, or trauma 1, 5

Optional Adjunctive Therapy

• Systemic corticosteroids (prednisone 40 mg daily for 7 days) can be considered in non-diabetic adult patients to hasten resolution by 1 day 1, 2
• Do NOT use corticosteroids in diabetic patients despite potential benefit in non-diabetics 2

Hospitalization Criteria

Admit patients with: 1, 2

• SIRS criteria (fever, altered mental status, hemodynamic instability)
• Concern for deeper or necrotizing infection
• Severe immunocompromise
• Poor adherence to outpatient therapy
• Failure of outpatient treatment after 24-48 hours

For hospitalized patients requiring parenteral therapy: 1

• Cefazolin is the preferred IV first-generation cephalosporin
• Nafcillin is an alternative penicillinase-resistant penicillin
• Vancomycin plus piperacillin-tazobactam or a carbapenem for severely compromised patients with SIRS 1, 2

Critical Pitfalls to Avoid

• Do not routinely add MRSA coverage for typical non-purulent cellulitis without specific risk factors - this is the most common error 2, 7, 8
• Do not automatically extend treatment to 10 days - only extend if no clinical improvement after 5 days 1, 2
• Do not neglect elevation of the extremity - this simple measure significantly accelerates improvement 1
• Do not miss interdigital toe web abnormalities - failure to examine and treat these leads to recurrence 1, 2
• Do not obtain blood cultures routinely - they are positive in only 5% of cases and unnecessary for typical cellulitis 2

When First-Line Therapy Fails

If no improvement after 48-72 hours of appropriate β-lactam therapy: 2

• Add empiric MRSA coverage immediately with TMP-SMX, doxycycline, or clindamycin
• Consider alternative diagnoses: deep vein thrombosis, venous stasis dermatitis, contact dermatitis, abscess requiring drainage, necrotizing infection 2, 10
• Obtain blood cultures and consider wound culture if any drainage present 2
• For hospitalized patients with treatment failure, switch to vancomycin 15-20 mg/kg IV every 8-12 hours 2

Prevention of Recurrence

For patients with 3-4 episodes per year despite treating predisposing factors: 1, 2

• Prophylactic antibiotics: oral penicillin or erythromycin twice daily for 4-52 weeks, OR intramuscular benzathine penicillin 1.2 MU every 2-4 weeks
• Continue prophylaxis as long as predisposing factors persist 1