What are the antibiotics of choice for treating cellulitis?

Antibiotics of Choice for Cellulitis

First-Line Treatment for Typical Nonpurulent Cellulitis

For typical nonpurulent cellulitis, use cephalexin 500 mg orally every 6 hours or dicloxacillin 250-500 mg orally every 6 hours for 5 days if clinical improvement occurs—MRSA coverage is NOT needed and represents overtreatment in 96% of cases. 1, 2

• Beta-lactam monotherapy (penicillinase-resistant penicillins or first-generation cephalosporins) is the IDSA-recommended standard of care with Grade A-I evidence, achieving 96% success rates in typical cellulitis 1, 2
• Alternative oral beta-lactams include penicillin V 250-500 mg four times daily, amoxicillin, or amoxicillin-clavulanate 875/125 mg twice daily 1, 2
• For hospitalized patients requiring IV therapy, cefazolin 1-2 g IV every 8 hours is the preferred agent, with nafcillin or oxacillin 2 g IV every 6 hours as alternatives 1, 2

Treatment Duration

• Treat for exactly 5 days if clinical improvement is evident—extending beyond 5 days is only indicated if symptoms have NOT improved within this timeframe 1, 2, 3
• Five-day courses are equally effective as 10-day courses for uncomplicated cellulitis based on high-quality randomized controlled trial evidence 1, 3

When to Add MRSA Coverage (Specific Risk Factors Only)

MRSA is an unusual cause of typical cellulitis and routine coverage is unnecessary—reserve MRSA-active agents ONLY for these specific scenarios: 1, 2

• Penetrating trauma or injection drug use 1, 2
• Purulent drainage or exudate visible on examination 1, 2
• Evidence of MRSA infection elsewhere or known nasal MRSA colonization 1, 2
• Systemic inflammatory response syndrome (SIRS): fever >38°C, tachycardia >90 bpm, hypotension, or altered mental status 1, 2
• Failure to respond to beta-lactam therapy after 48-72 hours 1, 2

MRSA Coverage Options When Indicated

• Clindamycin monotherapy 300-450 mg orally every 6 hours provides single-agent coverage for both streptococci and MRSA (use only if local resistance <10%) 1, 2
• Trimethoprim-sulfamethoxazole (TMP-SMX) 1-2 DS tablets twice daily PLUS a beta-lactam (cephalexin, penicillin, or amoxicillin)—never use TMP-SMX as monotherapy due to inadequate streptococcal coverage 1, 2, 4
• Doxycycline 100 mg twice daily PLUS a beta-lactam—never use doxycycline alone as its streptococcal activity is unreliable 1, 2

Evidence Supporting Selective MRSA Coverage

• A landmark randomized controlled trial demonstrated that adding TMP-SMX to cephalexin provided NO additional benefit for pure cellulitis without abscess: 85% cure rate with combination therapy vs 82% with cephalexin alone (risk difference 2.7%, 95% CI -9.3% to 15%, P=0.66) 4
• However, in MRSA-prevalent areas, antibiotics without CA-MRSA activity had 4.22 times higher odds of treatment failure (95% CI 2.25-7.92) when MRSA was actually present 1, 5
• This apparent contradiction resolves when recognizing that typical nonpurulent cellulitis is caused by streptococci in the vast majority of cases, while MRSA causes purulent infections 6, 7, 4

Penicillin Allergy Considerations

• Clindamycin 300-450 mg orally every 6 hours is the optimal choice for penicillin-allergic patients, as 99.5% of S. pyogenes strains remain susceptible 1
• Alternative options include doxycycline 100 mg twice daily (though streptococcal coverage is less reliable) or fluoroquinolones (levofloxacin 500 mg daily) reserved for specific scenarios 1, 2

Severe Cellulitis Requiring Hospitalization

Hospitalize immediately if any of these criteria are present: 1, 2

• SIRS criteria (fever, tachycardia >90, hypotension, altered mental status) 1, 2
• Severe pain out of proportion to examination findings (suggests necrotizing infection) 1, 2
• Rapid progression, skin anesthesia, gas in tissue, or bullous changes 1, 2
• Severe immunocompromise, neutropenia, or failure of outpatient therapy after 24-48 hours 1, 2

IV Antibiotic Regimens for Severe Cellulitis

• For severe cellulitis with systemic toxicity or suspected necrotizing fasciitis: Vancomycin 15-20 mg/kg IV every 8-12 hours PLUS piperacillin-tazobactam 3.375-4.5 g IV every 6 hours (or a carbapenem) 1, 2
• For complicated cellulitis requiring MRSA coverage: Vancomycin 15-20 mg/kg IV every 8-12 hours (A-I evidence), with alternatives including linezolid 600 mg IV twice daily, daptomycin 4 mg/kg IV once daily, or telavancin 10 mg/kg IV once daily 1, 2
• For documented group A streptococcal necrotizing fasciitis: Penicillin plus clindamycin is the specific recommended combination 2

Essential Adjunctive Measures (Often Neglected)

• Elevate the affected extremity above heart level for at least 30 minutes three times daily to promote gravity drainage of edema—this hastens improvement and is critical yet frequently overlooked 1, 2
• Examine interdigital toe spaces carefully for tinea pedis, fissuring, scaling, or maceration—treating these eradicates colonization and reduces recurrence risk 1, 2
• Treat predisposing conditions including venous insufficiency (compression stockings after acute infection resolves), lymphedema, eczema, and obesity 1, 2
• Consider systemic corticosteroids (prednisone 40 mg daily for 7 days) in non-diabetic adults to hasten resolution, though evidence is limited—avoid in diabetic patients 1, 2

Prevention of Recurrent Cellulitis

• Annual recurrence rates are 8-20% in patients with previous leg cellulitis 2
• For patients with 3-4 episodes per year despite treating predisposing factors, consider prophylactic antibiotics: oral penicillin V 250 mg twice daily or erythromycin 250 mg twice daily for 4-52 weeks, or intramuscular benzathine penicillin every 2-4 weeks 1, 2

Critical Pitfalls to Avoid

• Do NOT routinely add MRSA coverage for typical nonpurulent cellulitis without specific risk factors—this represents overtreatment in 96% of cases and increases antibiotic resistance 1, 2, 4
• Do NOT use TMP-SMX or doxycycline as monotherapy for typical cellulitis—their streptococcal coverage is inadequate and must be combined with a beta-lactam 1, 2
• Do NOT automatically extend treatment beyond 5 days—only extend if clinical improvement has NOT occurred within this timeframe 1, 2, 3
• Do NOT delay surgical consultation if any signs of necrotizing infection are present (severe pain out of proportion, rapid progression, skin anesthesia, gas in tissue)—these progress rapidly and require emergent debridement 1, 2
• Do NOT assume treatment failure means MRSA without considering alternatives: abscess requiring drainage, deep vein thrombosis mimicking cellulitis, or other cellulitis mimickers (venous stasis dermatitis, contact dermatitis, eczema) 1, 6

Monitoring and Reassessment

• Reassess within 24-48 hours for outpatients to ensure clinical improvement 1, 2
• If no improvement with appropriate first-line antibiotics, consider resistant organisms (add MRSA coverage), cellulitis mimickers, or underlying complications 1, 2
• Blood cultures are positive in only 5% of cases and are unnecessary for typical cellulitis—obtain only in patients with severe systemic features, malignancy, neutropenia, or unusual predisposing factors 1