Best Antibiotics for Cellulitis
For non-purulent cellulitis, first-line treatment should include cephalexin, penicillin, or clindamycin (for penicillin-allergic patients), targeting the most common causative organisms (β-hemolytic streptococci and methicillin-sensitive Staphylococcus aureus). 1, 2
Antibiotic Selection Algorithm
First-line options for uncomplicated cellulitis:
- Cephalexin (500mg orally 4 times daily) - targets β-hemolytic streptococci and methicillin-sensitive S. aureus 2
- Penicillin - effective against streptococcal species 1
- Clindamycin (600mg orally three times daily) - covers both β-hemolytic streptococci and provides good tissue penetration 2, 3
When to use MRSA coverage:
Add or switch to an MRSA-active agent when the patient has:
- Penetrating trauma
- Evidence of MRSA infection elsewhere
- Nasal colonization with MRSA
- History of injection drug use
- Systemic inflammatory response syndrome
- Failed initial therapy 1, 2
MRSA-active options include:
- Clindamycin (if local resistance rates are low)
- Trimethoprim-sulfamethoxazole
- Linezolid
- Vancomycin (for severe cases requiring IV therapy) 2
Duration of Therapy
The optimal duration for uncomplicated cellulitis is 5-7 days 1. Several studies support shorter courses:
- The NICE guideline recommends 5-7 days 1
- Studies comparing 5 vs 10 days of therapy with fluoroquinolones showed no significant differences in outcomes 1
- Research comparing 6 days of tedizolid with 10 days of linezolid showed similar clinical responses 1
For diabetic patients or those with comorbidities, standard duration is 7-14 days, with possible extension to 3-4 weeks for slow-resolving infections 2.
Route of Administration
Oral antibiotics are appropriate for most cases of cellulitis. A 2020 study showed that patients given only oral therapy were more likely to have improved at day 5 compared to those given intravenous therapy, with similar outcomes at days 10 and 30 4.
Special Considerations
MRSA Prevalence
In areas with high MRSA prevalence, empiric therapy with MRSA-active antibiotics may be warranted. A study showed that trimethoprim-sulfamethoxazole had significantly higher success rates than cephalexin (91% vs 74%) in a setting where 62% of positive cultures were MRSA 5.
Diabetic Patients
Diabetic patients require:
- More careful evaluation for deep tissue involvement
- Assessment for osteomyelitis
- Consideration of imaging (preferably MRI) if no improvement after 5 days 2
Prevention of Recurrence
For patients with recurrent cellulitis:
- Identify and treat predisposing conditions (tinea pedis, venous eczema, edema)
- Consider prophylactic antibiotics for patients with 3-4 episodes per year 2
Common Pitfalls to Avoid
Failing to distinguish between purulent and non-purulent cellulitis: Purulent SSTIs often require incision and drainage, while non-purulent cellulitis responds to antibiotics alone 1.
Unnecessary MRSA coverage: Not all cellulitis requires MRSA coverage. A randomized controlled trial showed that adding trimethoprim-sulfamethoxazole to cephalexin did not improve outcomes in patients with non-purulent cellulitis 6.
Prolonged antibiotic courses: Evidence suggests that shorter courses (5-7 days) are as effective as longer courses for uncomplicated cellulitis 1, 4.
Overlooking underlying conditions: Identifying and treating predisposing conditions (eczema, edema, venous insufficiency) is essential for preventing recurrence 2.
Inadequate follow-up: If no improvement is seen after 5 days, consider extending treatment duration, changing antibiotics, or reevaluating for deeper infection 2.