What is the best initial antibiotic for treating cellulitis?

Best Initial Antibiotic for Cellulitis

For typical uncomplicated cellulitis, start with oral cephalexin 500 mg four times daily or dicloxacillin 250-500 mg every 6 hours for 5 days—beta-lactam monotherapy is successful in 96% of cases and MRSA coverage is unnecessary unless specific risk factors are present. 1

First-Line Treatment Algorithm

Standard beta-lactam monotherapy is the evidence-based standard of care for typical nonpurulent cellulitis 1:

• Oral options (choose one):

  • Cephalexin 500 mg every 6 hours 1, 2
  • Dicloxacillin 250-500 mg every 6 hours 1
  • Amoxicillin 1
  • Penicillin V 250-500 mg four times daily 1

• IV options for hospitalized patients:

  • Cefazolin 1-2 g IV every 8 hours (preferred) 1
  • Nafcillin or oxacillin 2 g IV every 6 hours 1

Treatment duration: Exactly 5 days if clinical improvement occurs; extend only if symptoms have not improved within this timeframe 1. This represents a major shift from traditional 7-14 day courses, supported by high-quality randomized controlled trial evidence 1.

When to Add MRSA Coverage

Do NOT routinely add MRSA coverage—MRSA is an uncommon cause of typical cellulitis even in high-prevalence settings 1, 3. Add MRSA-active antibiotics ONLY when these specific risk factors are present 1:

• Penetrating trauma or injection drug use 1
• Purulent drainage or exudate 1
• Evidence of MRSA infection elsewhere or known nasal colonization 1
• Systemic inflammatory response syndrome (SIRS): fever, tachycardia, hypotension 1
• Failure to respond to beta-lactam therapy after 48-72 hours 1

MRSA coverage options when indicated 1:

• Clindamycin 300-450 mg orally every 6 hours (covers both streptococci and MRSA as monotherapy—no combination needed) 1
• Trimethoprim-sulfamethoxazole (TMP-SMX) 1-2 DS tablets twice daily PLUS a beta-lactam 1
• Doxycycline 100 mg twice daily PLUS a beta-lactam 1

Critical pitfall: Never use TMP-SMX or doxycycline as monotherapy for typical cellulitis—they lack reliable activity against beta-hemolytic streptococci 1.

Evidence Supporting Beta-Lactam Monotherapy

The strength of this recommendation comes from multiple converging lines of evidence:

• Beta-lactam treatment succeeds in 96% of patients with typical cellulitis 1, 3
• When organisms are identified (only 15-20% of cases), most are β-hemolytic streptococci or methicillin-sensitive S. aureus 3, 4
• Adding MRSA coverage to beta-lactam therapy provides no additional benefit in typical cases 1
• A retrospective cohort study in Hawaii (high MRSA prevalence area) found that antibiotics without MRSA activity had 4.22 times higher odds of treatment failure (95% CI 2.25-7.92), but this was specifically in a MRSA-prevalent setting with purulent features 5—not applicable to typical nonpurulent cellulitis 1

Severe Cellulitis Requiring Hospitalization

Hospitalize and use broad-spectrum combination therapy if any of these warning signs are present 1:

• Systemic toxicity: fever, hypotension, tachycardia, altered mental status 1
• Rapid progression or concern for necrotizing fasciitis 1
• Severe immunocompromise or neutropenia 1

Recommended IV combination regimens 1:

• Vancomycin 15-20 mg/kg IV every 8-12 hours PLUS piperacillin-tazobactam 3.375-4.5 g IV every 6 hours 1
• Vancomycin PLUS a carbapenem 1
• Linezolid 600 mg IV twice daily PLUS piperacillin-tazobactam 1

Duration for severe infections: 7-14 days guided by clinical response 1

Essential Adjunctive Measures

These non-antibiotic interventions significantly hasten improvement 1:

• Elevate the affected extremity above heart level for at least 30 minutes three times daily to promote gravity drainage 1
• Examine interdigital toe spaces for tinea pedis, fissuring, or maceration—treating these eradicates colonization and reduces recurrence 1
• Address predisposing conditions: venous insufficiency, lymphedema, chronic edema, obesity 1

Common Pitfalls to Avoid

• Don't reflexively add MRSA coverage simply because the patient is hospitalized or because community MRSA rates are high—typical nonpurulent cellulitis rarely involves MRSA 1
• Don't extend treatment beyond 5 days automatically—only extend if clinical improvement has not occurred 1
• Don't use combination therapy (TMP-SMX plus cephalexin) for pure cellulitis without abscess—it's no more efficacious than cephalexin alone 1
• Don't delay reassessment—evaluate within 24-48 hours to verify clinical response, as treatment failure rates of 21% have been reported with some regimens 1

Penicillin Allergy Considerations

For patients with penicillin/cephalosporin allergy 1:

• Clindamycin 300-450 mg every 6 hours (covers both streptococci and MRSA) 1
• Levofloxacin 500 mg daily (reserve for true beta-lactam allergies due to stewardship concerns) 1

Important: Patients with cephalosporin allergy can often receive penicillins with dissimilar side chains, and carbapenems can be safely used in cephalosporin-allergic patients 1.