First-Line Antibiotics for Cellulitis
For typical non-purulent cellulitis, start with oral antibiotics targeting beta-hemolytic streptococci: penicillin, amoxicillin, dicloxacillin, or cephalexin for 5 days. 1, 2
Pathogen-Directed Approach
The vast majority of cellulitis cases are caused by beta-hemolytic streptococci, with Staphylococcus aureus playing a secondary role unless there is penetrating trauma or an underlying abscess. 1, 2 This fundamental principle drives antibiotic selection—streptococcal coverage is the priority for uncomplicated cases. 1
First-Line Oral Antibiotics for Mild-Moderate Cellulitis
- Preferred agents: Penicillin, amoxicillin, dicloxacillin, or cephalexin 1, 2
- Treatment duration: 5 days initially, extending only if no improvement is evident 1, 2
- For penicillin-allergic patients: Clindamycin, erythromycin, or levofloxacin 1, 2
The American College of Physicians and Infectious Diseases Society of America both endorse this streptococcal-focused approach for non-purulent cellulitis. 1 Clindamycin is FDA-approved for serious skin and soft tissue infections caused by susceptible streptococci and staphylococci, and should be reserved for penicillin-allergic patients. 3
When to Add MRSA Coverage
Do NOT routinely cover MRSA for typical non-purulent cellulitis. 1, 4 However, empiric MRSA coverage is warranted when specific risk factors are present:
- Purulent drainage or exudate without a drainable abscess 2
- Penetrating trauma 1
- Evidence of MRSA infection elsewhere or nasal colonization 1
- Injection drug use 1
- Systemic inflammatory response syndrome (SIRS) 1
- High-risk populations: athletes, prisoners, military recruits, long-term care residents, men who have sex with men 5
MRSA-active regimens include:
- Clindamycin alone 2
- Trimethoprim-sulfamethoxazole (TMP-SMX) plus a beta-lactam (e.g., amoxicillin) 1, 2
- Tetracyclines plus a beta-lactam 1, 2
- Linezolid alone 2
In high MRSA-prevalence areas, trimethoprim-sulfamethoxazole demonstrated significantly higher treatment success rates (91%) compared to cephalexin (74%) in outpatients with cellulitis. 6 However, this should not change the guideline-based approach for typical non-purulent cases where streptococcal coverage remains paramount. 1, 2
Severe or Complicated Cellulitis
For patients requiring hospitalization or with severe systemic features:
- IV vancomycin for MRSA and streptococcal coverage 1
- Alternative IV options: linezolid, daptomycin, telavancin 1
- For severely compromised patients: Vancomycin plus piperacillin-tazobactam or a carbapenem (imipenem/meropenem) 1
- Treatment duration: 7-14 days based on clinical response 1, 2
Critical Adjunctive Measures
- Elevate the affected extremity to promote drainage of edema and inflammatory mediators 1, 2
- Examine and treat interdigital toe spaces for tinea pedis, fissuring, or maceration that harbor pathogens 1, 2
- Address predisposing conditions: edema, obesity, venous insufficiency 1
- Consider systemic corticosteroids (prednisone 40 mg daily for 7 days) in non-diabetic adults to hasten resolution 1, 2
Common Pitfalls to Avoid
- Over-treating with MRSA coverage in typical non-purulent cellulitis—this is unnecessary and promotes resistance 1, 4
- Failing to examine toe web spaces—this is where many predisposing infections originate 1, 2
- Not elevating the affected area—this simple measure significantly delays improvement 1, 2
- Inadequate treatment duration—extend beyond 5 days only if clinical improvement is absent 1, 2
- Obtaining routine cultures—blood or tissue cultures are not recommended for typical cases and have poor yield 1, 4
Diagnostic Considerations
Blood cultures should be reserved for patients with malignancy, severe systemic features, or unusual predisposing factors. 1 The diagnosis remains clinical, based on acute onset of erythema, warmth, swelling, and tenderness. 5, 4 Many conditions mimic cellulitis (venous stasis dermatitis, contact dermatitis, lymphedema), so consider alternative diagnoses if patients fail appropriate first-line therapy. 5, 4