Treatment of Cellulitis
First-Line Antibiotic Therapy
For typical uncomplicated cellulitis, beta-lactam monotherapy is the standard of care and achieves 96% success rates without requiring MRSA coverage. 1
Recommended Oral Agents
- Cephalexin 500 mg four times daily is the preferred first-line agent 1
- Dicloxacillin 250-500 mg every 6 hours provides excellent streptococcal and MSSA coverage 1
- Amoxicillin is equally effective for typical nonpurulent cellulitis 1
- Penicillin V 250-500 mg four times daily offers targeted streptococcal coverage 1
- Amoxicillin-clavulanate 875/125 mg twice daily is appropriate for bite-associated cellulitis or when broader coverage is desired 1
Intravenous Options for Hospitalized Patients
- Cefazolin 1-2 g IV every 8 hours is the preferred IV beta-lactam 1
- Nafcillin 2 g IV every 6 hours or oxacillin 2 g IV every 6 hours are alternatives 1
The Infectious Diseases Society of America emphasizes that MRSA is an uncommon cause of typical cellulitis, even in hospitals with high MRSA prevalence, making routine MRSA coverage unnecessary 1. Beta-lactam treatment succeeds in 96% of patients, confirming that empiric MRSA coverage is usually inappropriate 1, 2, 3.
Treatment Duration
Treat for exactly 5 days if clinical improvement occurs; extend only if symptoms have not improved within this timeframe. 1
This represents a paradigm shift from traditional 7-14 day courses 1. Five-day courses are as effective as 10-day courses for uncomplicated cellulitis, supported by high-quality randomized controlled trial evidence 1. The key decision point is clinical improvement—if warmth and tenderness have resolved, erythema is improving, and the patient is afebrile, stop antibiotics after 5 days 1.
Common pitfall: Extending treatment to 10-14 days based on residual erythema alone is inappropriate, as some inflammation persists even after bacterial eradication 1.
When to Add MRSA Coverage
MRSA-active antibiotics should be added ONLY when specific risk factors are present 1:
Indications for MRSA Coverage
- Penetrating trauma or injection drug use 1
- Purulent drainage or exudate 1
- Evidence of MRSA infection elsewhere or known nasal MRSA colonization 1
- Systemic inflammatory response syndrome (SIRS) with fever, tachycardia, or hypotension 1
- Failure to respond to beta-lactam therapy after 48-72 hours 1
MRSA-Active Regimens
For outpatients requiring MRSA coverage:
- Clindamycin 300-450 mg orally every 6 hours provides single-agent coverage for both streptococci and MRSA (use only if local resistance <10%) 1
- Trimethoprim-sulfamethoxazole (TMP-SMX) 1-2 DS tablets twice daily PLUS a beta-lactam (cephalexin, penicillin, or amoxicillin) 1
- Doxycycline 100 mg orally twice daily PLUS a beta-lactam 1
Critical caveat: Never use TMP-SMX or doxycycline as monotherapy for typical cellulitis, as their activity against beta-hemolytic streptococci is unreliable 1.
For hospitalized patients with complicated cellulitis:
- Vancomycin 15-20 mg/kg IV every 8-12 hours (A-I evidence) 1
- Linezolid 600 mg IV twice daily (A-I evidence) 1
- Daptomycin 4 mg/kg IV once daily (A-I evidence) 1
- Clindamycin 600 mg IV every 8 hours if local resistance <10% (A-III evidence) 1
Severe Cellulitis with Systemic Toxicity
For patients with signs of systemic toxicity, rapid progression, or suspected necrotizing fasciitis, mandatory broad-spectrum combination therapy is required. 1
Recommended IV Combination Regimens
- Vancomycin 15-20 mg/kg IV every 8-12 hours PLUS piperacillin-tazobactam 3.375-4.5 g IV every 6 hours 1
- Linezolid 600 mg IV twice daily PLUS piperacillin-tazobactam 1
- Vancomycin PLUS a carbapenem (meropenem 1 g IV every 8 hours) 1
- Vancomycin PLUS ceftriaxone 2 g IV daily and metronidazole 500 mg IV every 8 hours 1
Duration for Severe Infections
- 7-14 days of therapy guided by clinical response 1
- For necrotizing fasciitis or infections requiring surgical debridement, continue for 7-14 days 1
Warning signs requiring emergent surgical consultation: severe pain out of proportion to examination, skin anesthesia, rapid progression, gas in tissue, systemic toxicity, or bullous changes 1.
Hospitalization Criteria
Admit patients with any of the following 1:
- SIRS criteria: fever >38°C, tachycardia >90 bpm, tachypnea >24 rpm, or altered mental status 1
- Hypotension or hemodynamic instability 1
- Severe immunocompromise or neutropenia 1
- Concern for deeper or necrotizing infection 1
- Failure of outpatient treatment after 24-48 hours 1
Essential Adjunctive Measures
Elevation of Affected Extremity
Elevate the affected extremity above heart level for at least 30 minutes three times daily to promote gravitational drainage of edema and inflammatory substances 1. This intervention hastens improvement and is often neglected 1.
Treat Predisposing Conditions
- Examine interdigital toe spaces for tinea pedis, fissuring, scaling, or maceration—treating these eradicates colonization and reduces recurrence risk 1
- Address venous insufficiency and lymphedema with compression stockings once acute infection resolves 1
- Manage chronic edema, obesity, eczema, and toe web abnormalities 1
Systemic Corticosteroids
Consider prednisone 40 mg daily for 7 days in non-diabetic adults to potentially hasten resolution, though evidence is limited (weak recommendation, moderate evidence) 1. Avoid corticosteroids in diabetic patients despite potential benefit in non-diabetics 1.
Special Populations
Pediatric Dosing
- Cephalexin: standard pediatric dosing 1
- Vancomycin 15 mg/kg IV every 6 hours for hospitalized children with complicated cellulitis 1
- Clindamycin 10-13 mg/kg/dose IV every 6-8 hours if stable, no bacteremia, and local resistance <10% 1
- Doxycycline 2 mg/kg/dose orally every 12 hours for children >8 years and <45 kg (never use in children <8 years due to tooth discoloration) 1
Elderly Patients
No dosage adjustment necessary up to 2 grams per day, provided there is no severe renal or hepatic impairment 1. Elevation of the affected leg is especially important in elderly patients with heart failure to promote drainage and reduce edema 1.
Diabetic Patients
- Longer treatment duration may be required compared to non-diabetic patients 1
- Avoid systemic corticosteroids despite evidence showing benefit in non-diabetic adults 1
- Consider broader coverage with amoxicillin-clavulanate, second or third-generation cephalosporins, or fluoroquinolones for moderate diabetic foot infections 1
Prevention of Recurrent Cellulitis
Annual recurrence rates are 8-20% in patients with previous leg cellulitis 1, 4.
Prophylactic Antibiotics
For patients with 3-4 episodes per year despite optimal management of risk factors, consider prophylactic antibiotics: 1
- Oral penicillin V 250 mg-1 g twice daily for 4-52 weeks 1
- Oral erythromycin 250 mg twice daily 1
- Intramuscular benzathine penicillin every 2-4 weeks 1
Antimicrobial prophylaxis can markedly reduce the frequency of relapse, with penicillin remaining the drug of choice 4.
Common Pitfalls to Avoid
- Do not routinely add MRSA coverage for typical cellulitis without specific risk factors 1
- Do not use doxycycline or TMP-SMX as monotherapy for typical cellulitis due to unreliable streptococcal coverage 1
- Do not extend treatment beyond 5 days automatically—only extend if clinical improvement has not occurred 1
- Do not delay surgical consultation if any signs of necrotizing infection are present 1
- Do not use clindamycin as first-line in CKD patients due to nephrotoxicity concerns 1
- Do not assume treatment failure means MRSA without considering alternatives such as abscess requiring drainage, deep vein thrombosis mimicking cellulitis, or necrotizing infection 1
Monitoring Response to Therapy
Reassess within 24-48 hours for outpatients to ensure clinical improvement 1. If no improvement with appropriate first-line antibiotics, consider resistant organisms (add MRSA coverage), cellulitis mimickers (venous stasis dermatitis, contact dermatitis, DVT), or underlying complications (abscess, necrotizing infection) 1, 2, 3.
Blood cultures are positive in only 5% of cases and are unnecessary for typical cellulitis 1. Obtain blood cultures and consider tissue cultures only in patients with severe systemic features, malignancy, neutropenia, or unusual predisposing factors 1.