Best Antibiotic for Cellulitis
For typical uncomplicated cellulitis, use cephalexin (a first-generation cephalosporin) or dicloxacillin (a penicillinase-resistant penicillin) for 5-6 days, targeting streptococci as the primary pathogen. 1, 2
First-Line Therapy for Typical Cellulitis
- Cephalexin (first-generation cephalosporin) is the preferred first-line agent with Grade A-I evidence from IDSA guidelines 2
- Dicloxacillin (penicillinase-resistant semisynthetic penicillin) is an equally effective alternative with Grade A-I evidence 2
- These agents target streptococci, which are the predominant pathogens in typical cellulitis without purulent drainage 1
Treatment Duration
- A 5-6 day course is as effective as 10 days for uncomplicated cellulitis if clinical improvement occurs 1, 2
- Extend treatment only if the infection has not improved within 5 days 1
When MRSA Coverage is NOT Needed
MRSA is an unusual cause of typical cellulitis and routine coverage is unnecessary 2. The evidence strongly supports this:
- Two large randomized controlled trials showed that adding trimethoprim-sulfamethoxazole to cephalexin provided no benefit over cephalexin alone for uncomplicated cellulitis 3, 4
- In the 2017 JAMA trial (n=496), clinical cure rates were 85.5% with cephalexin alone vs 83.5% with cephalexin plus TMP-SMX (no significant difference) 4
When to Add MRSA Coverage
Add MRSA-active antibiotics only in these specific high-risk scenarios: 1, 2
- Penetrating trauma
- Purulent drainage present
- Evidence of MRSA infection elsewhere
- Nasal colonization with MRSA documented
- Injection drug use
- Systemic inflammatory response syndrome (SIRS) present
MRSA Coverage Options (When Indicated)
Clindamycin 300-450 mg orally four times daily is the preferred single agent, as it covers both streptococci and MRSA 2, 5, 6
Alternative: Trimethoprim-sulfamethoxazole PLUS a β-lactam (cephalexin, penicillin, or amoxicillin) 2
For Penicillin/Cephalosporin Allergic Patients
- Clindamycin is the preferred option, with 99.5% of S. pyogenes strains remaining susceptible 2, 5
- For severe allergies requiring parenteral therapy, use vancomycin, linezolid, or telavancin 5
Route of Administration
- Oral antibiotics are as effective as IV antibiotics for cellulitis of similar severity 7
- Reserve IV therapy only for patients with SIRS, altered mental status, hemodynamic instability, or inability to take oral medications 1
- Patients given oral-only therapy were more likely to have improved at day 5 compared to those given IV therapy in a 323-patient analysis 7
Critical Pitfall to Avoid
Do not routinely add MRSA coverage for typical cellulitis. This is the most common prescribing error. 2 Despite the prevalence of community-associated MRSA in purulent skin infections (abscesses), it remains an uncommon cause of non-purulent cellulitis. Two high-quality RCTs definitively showed no benefit from adding MRSA coverage to standard therapy for uncomplicated cellulitis 3, 4, yet clinicians continue to overprescribe MRSA-active agents.
Adjunctive Measures
- Elevate the affected extremity to promote drainage of edema 1, 2, 5
- Examine and treat interdigital toe spaces for tinea pedis, as this eradicates pathogen colonization and reduces recurrence 1, 2
- Treat predisposing conditions including venous insufficiency, eczema, and edema 1, 2, 5
- Consider systemic corticosteroids (prednisone 40 mg daily for 7 days) in non-diabetic adults to potentially hasten resolution 1, 2
Hospitalization Criteria
- SIRS or hemodynamic instability
- Altered mental status
- Concern for deeper or necrotizing infection
- Severe immunocompromise
- Failed outpatient therapy
- Poor adherence anticipated