What is the recommended treatment for a patient with uncomplicated cellulitis, considering potential penicillin allergy and varying severity of infection?

Treatment of Cellulitis

First-Line Antibiotic Therapy

For typical uncomplicated cellulitis, beta-lactam monotherapy is the standard of care and is successful in 96% of patients—MRSA coverage is NOT routinely needed. 1

Recommended Oral Agents for Uncomplicated Cellulitis

• Cephalexin 500 mg orally every 6 hours (four times daily) is the preferred first-line agent, providing excellent coverage against beta-hemolytic streptococci and methicillin-sensitive Staphylococcus aureus 1, 2
• Dicloxacillin 250-500 mg orally every 6 hours is equally effective as first-line therapy 1, 2
• Amoxicillin alone provides adequate streptococcal coverage for typical nonpurulent cellulitis 1
• Amoxicillin-clavulanate 875/125 mg twice daily is appropriate for bite-associated cellulitis or when broader coverage is desired 1, 2
• Penicillin V 250-500 mg orally four times daily is an alternative option 1

Intravenous Options for Hospitalized Patients

• Cefazolin 1-2 g IV every 8 hours is the preferred IV beta-lactam for hospitalized patients with uncomplicated cellulitis 1, 2
• Nafcillin 2 g IV every 6 hours or oxacillin 2 g IV every 6 hours are alternatives 1

Treatment Duration

Treat for exactly 5 days if clinical improvement has occurred; extend only if symptoms have not improved within this timeframe. 1, 3

• High-quality randomized controlled trial evidence demonstrates that 5-day courses are as effective as 10-day courses for uncomplicated cellulitis 1, 3
• The traditional 7-14 day courses are no longer necessary for uncomplicated cases 1
• Extending treatment to 10-14 days based on tradition rather than evidence increases antibiotic resistance without improving outcomes 1

When to Add MRSA Coverage

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

Specific Risk Factors Requiring MRSA Coverage

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

• Penetrating trauma or injection drug use 1, 2
• Purulent drainage or exudate (without a drainable abscess) 1, 2
• Evidence of MRSA infection elsewhere or known nasal MRSA colonization 1, 2
• Systemic inflammatory response syndrome (SIRS): fever >38°C, tachycardia >90 bpm, tachypnea >24 rpm, or altered mental status 1, 2
• Failure to respond to beta-lactam therapy after 48-72 hours 1, 2

MRSA-Active Regimens

When MRSA coverage is indicated:

• 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 rates are <10% 1, 2
• Trimethoprim-sulfamethoxazole (TMP-SMX) 1-2 double-strength tablets twice daily PLUS a beta-lactam (cephalexin, amoxicillin, or penicillin) 1, 2
• Doxycycline 100 mg orally twice daily PLUS a beta-lactam 1, 4
• Never use doxycycline or TMP-SMX as monotherapy for typical cellulitis, as their activity against beta-hemolytic streptococci is unreliable 1, 2

Management of Penicillin Allergy

For patients with penicillin allergy, clindamycin 300-450 mg orally every 6 hours is the optimal choice, providing single-agent coverage for both streptococci and MRSA without requiring combination therapy. 1, 2

• Cross-reactivity between penicillins and cephalosporins is only 2-4%, primarily based on R1 side chain similarity 1
• Cephalosporins with dissimilar side chains can be safely used in most penicillin-allergic patients 1
• For severe immediate-type penicillin allergy, use clindamycin or a fluoroquinolone (levofloxacin 500 mg daily) 1, 2

Severe Cellulitis Requiring Hospitalization

Indications for Hospitalization

Admit patients with any of the following:

• SIRS criteria: fever, hypotension, tachycardia, altered mental status 1, 2
• Severe immunocompromise or neutropenia 1
• Concern for deeper or necrotizing infection: severe pain out of proportion to examination, skin anesthesia, rapid progression, "wooden-hard" subcutaneous tissues, gas in tissue, or bullous changes 1, 2
• Failure of outpatient treatment after 24-48 hours 1, 2

Empiric IV Regimens for Severe Cellulitis

For patients with signs of systemic toxicity, rapid progression, or suspected necrotizing fasciitis, mandatory broad-spectrum combination therapy is required:

• Vancomycin 15-20 mg/kg IV every 8-12 hours PLUS piperacillin-tazobactam 3.375-4.5 g IV every 6 hours 1, 2
• Alternative combinations: vancomycin PLUS a carbapenem (meropenem 1 g IV every 8 hours) or vancomycin PLUS ceftriaxone 2 g IV daily and metronidazole 500 mg IV every 8 hours 1
• Linezolid 600 mg IV twice daily is an equally effective alternative to vancomycin (A-I evidence) 1
• Daptomycin 4 mg/kg IV once daily is another alternative (A-I evidence) 1
• Treatment duration for severe cellulitis is 7-14 days, individualized based on clinical response 1, 2

Essential Adjunctive Measures

Elevation of the affected extremity hastens improvement by promoting gravity drainage of edema and inflammatory substances—this is critical and often neglected. 1, 2

• Elevate the limb above heart level for at least 30 minutes three times daily 1
• Examine interdigital toe spaces carefully for tinea pedis, fissuring, scaling, or maceration—treating these eradicates colonization and reduces recurrent infection risk 1, 2
• Treat predisposing conditions: venous insufficiency, lymphedema, chronic edema, eczema, obesity 1, 2
• Systemic corticosteroids (prednisone 40 mg daily for 7 days) could be considered in non-diabetic adults, though evidence is limited—avoid in diabetic patients 1, 2

Common Pitfalls to Avoid

• Do not routinely add MRSA coverage for typical nonpurulent cellulitis without specific risk factors—this represents overtreatment and increases antibiotic resistance 1, 2
• Do not extend treatment beyond 5 days automatically—only extend if clinical improvement has not occurred 1, 3
• Do not use doxycycline or TMP-SMX as monotherapy for cellulitis, as streptococcal coverage will be inadequate 1, 2
• Do not delay surgical consultation if any signs of necrotizing infection are present—these infections progress rapidly and require debridement 1, 2
• Do not assume bilateral lower extremity erythema is cellulitis—consider venous stasis dermatitis, contact dermatitis, or lymphedema as mimickers 1, 5

Monitoring and Follow-Up

Reassess within 24-48 hours for outpatients to ensure clinical improvement. 1, 2

• If no improvement with appropriate first-line antibiotics, consider resistant organisms (add MRSA coverage), cellulitis mimickers (venous stasis, DVT), or underlying complications (abscess requiring drainage, necrotizing infection) 1, 2
• Blood cultures are positive in only 5% of cases and are unnecessary for typical cellulitis 1
• Obtain blood cultures only in patients with severe systemic features, malignancy, neutropenia, or unusual predisposing factors 1

Prevention of Recurrent Cellulitis

• Annual recurrence rates are 8-20% in patients with previous leg cellulitis 1
• For patients with 3-4 episodes per year despite treating predisposing factors, consider prophylactic antibiotics: oral penicillin V 250 mg twice daily or erythromycin 250 mg twice daily for 4-52 weeks 1, 2
• Address underlying venous insufficiency and lymphedema with compression stockings once acute infection resolves 1, 2