What is the recommended treatment for an adult patient with cellulitis, considering potential penicillin allergy and local resistance patterns?

Treatment for Cellulitis

For typical uncomplicated cellulitis, beta-lactam monotherapy with cephalexin 500 mg orally four times daily for 5 days is the standard of care, achieving 96% success rates without requiring MRSA coverage. 1

First-Line Antibiotic Selection

Beta-lactam monotherapy is the cornerstone of cellulitis treatment for nonpurulent cases without specific risk factors. 1 The most commonly recommended oral agents include:

• Cephalexin 500 mg orally every 6 hours (four times daily) 1
• Dicloxacillin 250-500 mg every 6 hours 1
• Amoxicillin (standard dosing) 1
• Penicillin V 250-500 mg four times daily 1

These agents provide excellent coverage against beta-hemolytic streptococci (especially Streptococcus pyogenes) and methicillin-sensitive Staphylococcus aureus, which are the primary pathogens in typical cellulitis. 1, 2

Treatment Duration

Treat for exactly 5 days if clinical improvement has occurred; extend only if symptoms have not improved within this timeframe. 1 This represents a significant departure from traditional 7-14 day courses, which are no longer necessary for uncomplicated cases. 1 The 5-day duration is supported by high-quality randomized controlled trial evidence showing equivalent efficacy to 10-day courses. 1, 3

When to Add MRSA Coverage

MRSA coverage should NOT be added reflexively for typical nonpurulent cellulitis, as MRSA is an uncommon cause even in high-prevalence settings. 1 Add MRSA-active antibiotics ONLY when specific risk factors are present:

• Penetrating trauma or injection drug use 1
• Purulent drainage or exudate 1
• Evidence of MRSA infection elsewhere or known MRSA colonization 1
• Systemic inflammatory response syndrome (SIRS) 1

When MRSA coverage is needed, use clindamycin 300-450 mg orally every 6 hours as monotherapy (covers both streptococci and MRSA), but only if local MRSA clindamycin resistance rates are <10%. 1 Alternative regimens include:

• Trimethoprim-sulfamethoxazole (1-2 double-strength tablets twice daily) PLUS a beta-lactam 1
• Doxycycline 100 mg orally twice daily PLUS a beta-lactam 1, 4

Critical caveat: Never use doxycycline or trimethoprim-sulfamethoxazole as monotherapy for typical cellulitis, as their activity against beta-hemolytic streptococci is unreliable. 1

Management of Penicillin Allergy

For patients with penicillin allergy:

• Cephalexin remains an option for most penicillin-allergic patients (except immediate hypersensitivity reactions), as cross-reactivity between penicillins and cephalosporins is only 2-4%. 1
• Clindamycin 300-450 mg orally every 6 hours is the optimal choice for patients allergic to both penicillins and sulfonamides, providing single-agent coverage for both streptococci and MRSA. 1
• Avoid cephalexin in patients with confirmed immediate-type amoxicillin allergy, as they share identical R1 side chains. 1

Severe Cellulitis Requiring Hospitalization

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
• Alternative combinations include vancomycin or linezolid PLUS a carbapenem, or ceftriaxone plus metronidazole 1
• Treatment duration for severe infections is 7-14 days, guided by clinical response 1

Hospitalization criteria include: 1

• Systemic inflammatory response syndrome (SIRS), fever, hypotension, or altered mental status
• Severe immunocompromise or neutropenia
• Failure of outpatient treatment

Essential Adjunctive Measures

Elevation of the affected extremity hastens improvement by promoting gravity drainage of edema and inflammatory substances—this is often neglected but critical. 1, 3

Additional measures include: 1

• Treating predisposing conditions: tinea pedis, toe web abnormalities, venous insufficiency, lymphedema, and chronic edema
• Examining interdigital toe spaces for fissuring, scaling, or maceration
• Systemic corticosteroids (prednisone 40 mg daily for 7 days) could be considered in non-diabetic adults, though evidence is limited 1

Common Pitfalls to Avoid

• Don't extend treatment unnecessarily beyond 5 days if clinical improvement has occurred 1
• Don't automatically add MRSA coverage for typical nonpurulent cellulitis without specific risk factors 1
• Don't continue ineffective antibiotics beyond 48 hours—if the patient is not improving, reassess for resistant organisms, deeper infection, or misdiagnosis 1
• Don't forget to examine interdigital toe spaces in lower-extremity cellulitis, as treating fissuring or maceration may reduce recurrence 1
• Don't use combination therapy when monotherapy is appropriate, as this increases adverse effects without improving outcomes 1

Special Populations

Diabetic Foot Cellulitis

Diabetic foot infections require broader coverage and longer duration: 1

• Mild infections: Amoxicillin-clavulanate, levofloxacin, or cephalexin
• Moderate infections: Amoxicillin-clavulanate, levofloxacin, ceftriaxone, or ampicillin-sulbactam
• Severe infections: Piperacillin-tazobactam, imipenem-cilastatin, or vancomycin plus ceftazidime

Older Adults

For older adults, the same 5-day treatment duration applies if clinical improvement occurs. 3 Elevation of the affected area is particularly important in this population to promote gravity drainage. 3 Address underlying conditions common in older adults, including venous insufficiency, tinea pedis, and prior trauma. 3

Prevention of Recurrent Cellulitis

For patients with 3-4 episodes per year despite optimal management of risk factors, consider prophylactic antibiotics: 1

• Oral penicillin V 250 mg twice daily
• Oral erythromycin 250 mg twice daily