Antibiotic Treatment for Cellulitis

First-Line Treatment for Typical Nonpurulent Cellulitis

Beta-lactam monotherapy is the standard of care for typical uncomplicated cellulitis, with a 96% success rate, and MRSA coverage is unnecessary in most cases. 1

Recommended Oral Agents

Cephalexin 500 mg orally every 6 hours (four times daily) is the preferred oral beta-lactam for typical nonpurulent cellulitis 1, 2
Dicloxacillin 250-500 mg orally every 6 hours provides excellent streptococcal and methicillin-sensitive S. aureus coverage 1, 3
Amoxicillin is an appropriate alternative beta-lactam option 1
Penicillin V 250-500 mg orally four times daily can be used for streptococcal coverage 1

Treatment Duration

Treat for exactly 5 days if clinical improvement occurs (warmth and tenderness resolved, erythema improving, patient afebrile) 1, 2, 4
Extend treatment only if symptoms have not improved within this 5-day timeframe—do not reflexively extend to 7-10 days based on residual erythema alone, as some inflammation persists even after bacterial eradication 1, 2
The landmark randomized controlled trial comparing 5-day versus 10-day levofloxacin courses showed identical 98% success rates at both 14 and 28 days 4

When to Add MRSA Coverage

MRSA coverage should be added only when specific risk factors are present, not routinely for all cellulitis. 1, 2

Specific MRSA Risk Factors

Penetrating trauma or injection drug use 1, 2
Purulent drainage or exudate (even without a drainable abscess) 5, 1, 2
Evidence of MRSA infection elsewhere or nasal MRSA colonization 1, 2
Systemic inflammatory response syndrome (SIRS) with fever >38°C, tachycardia >90 bpm, or tachypnea >24 rpm 1, 2
Failure to respond to beta-lactam therapy after 48-72 hours 5, 1

Oral Regimens for MRSA Coverage

When MRSA coverage is needed, choose one of these options:

Clindamycin 300-450 mg orally every 6 hours (four times daily) as monotherapy—covers both streptococci and MRSA, avoiding the need for combination therapy, but only use if local MRSA clindamycin resistance rates are <10% 5, 1, 2
Trimethoprim-sulfamethoxazole (TMP-SMX) 1-2 double-strength tablets twice daily PLUS a beta-lactam (such as cephalexin or amoxicillin)—TMP-SMX alone has unreliable streptococcal activity 5, 1, 2
Doxycycline 100 mg orally twice daily PLUS a beta-lactam—doxycycline alone lacks reliable beta-hemolytic streptococcal coverage 5, 1, 2
Linezolid 600 mg orally twice daily as monotherapy—covers both streptococci and MRSA but is expensive and typically reserved for complicated cases 5, 1

Critical caveat: The combination trial of cephalexin plus TMP-SMX versus cephalexin alone showed no benefit (85% vs 82% cure rates, p=0.66), confirming that MRSA coverage is unnecessary for typical cellulitis without purulent features 6

Hospitalized Patients and IV Therapy

Indications for Hospitalization

Systemic inflammatory response syndrome (SIRS) with fever, hypotension, or altered mental status 1, 2
Severe immunocompromise or neutropenia 1, 2
Concern for deeper or necrotizing infection (severe pain out of proportion to exam, skin anesthesia, rapid progression, "wooden-hard" tissues, gas in tissue, bullous changes) 1, 2
Failure of outpatient treatment or poor adherence 2

IV Antibiotic Options for Complicated Cellulitis

For hospitalized patients with complicated cellulitis requiring MRSA coverage:

Vancomycin 15-20 mg/kg IV every 8-12 hours is first-line with A-I level evidence 5, 1, 7
Linezolid 600 mg IV twice daily is equally effective (A-I evidence) 5, 1
Daptomycin 4 mg/kg IV once daily is an alternative (A-I evidence) 5, 1
Clindamycin 600 mg IV three times daily if local MRSA resistance <10% (A-III evidence) 5, 1

For uncomplicated cellulitis requiring hospitalization without MRSA risk factors:

Cefazolin 1-2 g IV every 8 hours is the preferred IV beta-lactam 1, 2
Nafcillin or oxacillin 2 g IV every 6 hours are alternatives 1
Modify to MRSA-active therapy only if no clinical response after 48 hours 5, 1

Treatment duration for hospitalized patients: 7-14 days, individualized based on clinical response 5, 1

Evidence note: Oral antibiotics are as effective as IV therapy for cellulitis of similar severity—recovery is not associated with route of administration 8

Severe Cellulitis with Systemic Toxicity or Suspected Necrotizing Infection

For patients with signs of systemic toxicity, rapid progression, or suspected necrotizing fasciitis, mandatory broad-spectrum combination therapy is required immediately. 1, 2

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, 2
Linezolid 600 mg IV twice daily PLUS piperacillin-tazobactam 1
Vancomycin PLUS a carbapenem (meropenem 1 g IV every 8 hours or imipenem) 1, 2
Vancomycin PLUS ceftriaxone 2 g IV daily and metronidazole 500 mg IV every 8 hours 1

For documented group A streptococcal necrotizing fasciitis: Penicillin plus clindamycin is the specific recommended combination 1

Treatment duration: 7-10 days minimum, with reassessment at 5 days 1

Surgical consultation: Obtain emergent surgical evaluation if any warning signs of necrotizing infection are present—these infections progress rapidly and require debridement 1

Special Populations and Situations

Penicillin/Cephalosporin Allergy

For true penicillin and cephalosporin allergies: Clindamycin 300-450 mg orally every 6 hours provides single-agent coverage for both streptococci and MRSA (if local resistance <10%) 1, 2
Cross-reactivity between penicillins and cephalosporins is only 2-4%, primarily based on R1 side chain similarity rather than the beta-lactam ring 1
Cephalexin shares identical R1 side chains with amoxicillin, so avoid cephalexin in patients with confirmed immediate-type amoxicillin allergy 1
Fluoroquinolones (levofloxacin 500 mg daily, moxifloxacin) can be used but lack adequate MRSA coverage and should be reserved for beta-lactam allergies 1, 2

Diabetic Foot Cellulitis

Diabetic foot infections are polymicrobial and require broader coverage and longer duration 1
For mild diabetic foot infections: Dicloxacillin, clindamycin, cephalexin, TMP-SMX, amoxicillin-clavulanate, or levofloxacin 1
For moderate diabetic foot infections: Amoxicillin-clavulanate, levofloxacin, ceftriaxone, ampicillin-sulbactam, or ertapenem 1
For severe diabetic foot infections: Piperacillin-tazobactam, imipenem-cilastatin, or vancomycin plus ceftazidime with or without metronidazole 1

Pediatric Considerations

Vancomycin 15 mg/kg IV every 6 hours is first-line for hospitalized children with complicated cellulitis 5, 1
Clindamycin 10-13 mg/kg/dose IV every 6-8 hours if stable, no bacteremia, and local resistance <10% 5, 1
Linezolid: 600 mg IV twice daily for children >12 years, or 10 mg/kg/dose IV every 8 hours for children <12 years 5, 1
Tetracyclines (doxycycline) should never be used in children <8 years of age due to tooth discoloration and bone growth effects 5, 1

Essential Adjunctive Measures

These non-antibiotic interventions are critical and often neglected:

Elevate the affected extremity above heart level for at least 30 minutes three times daily to promote gravity drainage of edema 1, 2
Examine interdigital toe spaces for tinea pedis, fissuring, scaling, or maceration—treating these eradicates colonization and reduces recurrent infection risk 1, 2
Treat predisposing conditions: venous insufficiency, lymphedema, chronic edema, obesity, eczema 1, 2
Consider systemic corticosteroids (prednisone 40 mg daily for 7 days) in non-diabetic adults, though evidence is limited 1, 2

Prevention of Recurrent Cellulitis

For patients with 3-4 episodes per year despite optimal management of risk factors:

Prophylactic penicillin V 250 mg orally twice daily for 4-52 weeks 1, 2
Prophylactic erythromycin 250 mg orally twice daily as an alternative 1, 2
Annual recurrence rates are 8-20% in patients with previous leg cellulitis 1

Common Pitfalls to Avoid

Do not routinely add MRSA coverage for typical cellulitis without specific risk factors—this represents overtreatment and increases antibiotic resistance 1, 2
Do not use doxycycline or TMP-SMX as monotherapy for cellulitis—their activity against beta-hemolytic streptococci is unreliable 5, 1, 2
Do not extend treatment to 10-14 days based on tradition—5 days is sufficient for uncomplicated cases with clinical improvement 1, 2, 4
Do not rely on oral antibiotics in patients with severe illness, nausea, vomiting, or intestinal hypermotility—these patients may not absorb therapeutic amounts 3
Do not combine multiple antibiotics when monotherapy is appropriate—this increases adverse effects without improving outcomes 1

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