What is the recommended antibiotic regimen for possible Methicillin-resistant Staphylococcus aureus (MRSA) cellulitis?

Recommended Antibiotic Regimen for Possible MRSA Cellulitis

Outpatient Oral Therapy

For outpatient cellulitis requiring MRSA coverage, prescribe trimethoprim-sulfamethoxazole (TMP-SMX) 1-2 double-strength tablets twice daily or doxycycline 100 mg twice daily as first-line therapy. 1

Key Decision Point: Purulent vs Non-Purulent

The critical distinction is whether the cellulitis is purulent (with abscess/drainage) or non-purulent (typical cellulitis without purulence):

• Purulent cellulitis strongly suggests MRSA and requires immediate MRSA coverage with TMP-SMX, doxycycline, or minocycline 2, 1
• Non-purulent cellulitis is more likely streptococcal and should initially be treated with a β-lactam (cephalexin 500 mg four times daily or dicloxacillin 500 mg four times daily) 1
• Add MRSA coverage to non-purulent cellulitis only if the patient fails β-lactam therapy within 48-72 hours or presents with systemic toxicity 1

Specific Oral Regimens for MRSA Coverage

• TMP-SMX: 1-2 double-strength tablets twice daily 2, 1
• Doxycycline: 100 mg twice daily 2, 1
• Minocycline: 200 mg loading dose, then 100 mg twice daily (equally effective alternative to TMP-SMX for purulent cellulitis) 1, 3
• Clindamycin: 300-450 mg three times daily, but only if local MRSA resistance rates are below 10% due to inducible resistance concerns 2, 1

Critical Caveat About Streptococcal Coverage

TMP-SMX and tetracyclines have excellent MRSA coverage but poorly defined activity against β-hemolytic streptococci, which remain common cellulitis pathogens 1. This is why empiric MRSA coverage for typical non-purulent cellulitis is not routinely recommended—a randomized controlled trial showed no benefit of adding TMP-SMX to cephalexin for uncomplicated cellulitis 4.

Inpatient IV Therapy

For hospitalized patients with cellulitis requiring MRSA coverage, vancomycin 15-20 mg/kg IV every 8-12 hours is the gold standard. 1, 5

Indications for Hospitalization

Admit patients with any of these high-risk features:

• Systemic signs of illness (fever >38°C, tachycardia >90 bpm, tachypnea >24 breaths/min, abnormal WBC) 2, 5
• Rapidly progressive infection 5
• Multiple sites of infection 5
• Significant comorbidities or immunocompromise 2, 5
• Abscess in difficult-to-drain locations 5
• Septic phlebitis 5

IV Antibiotic Options

• Vancomycin: 15-20 mg/kg IV every 8-12 hours (gold standard) 1, 5, 6
• Linezolid: 600 mg IV every 12 hours (equally effective alternative, superior in some MRSA studies) 5, 6
• Daptomycin: 4 mg/kg IV once daily 1, 5
• Clindamycin: 600 mg IV every 8 hours, only if local MRSA resistance <10% 1, 5

Dual Coverage for Severe Infections

For severe cellulitis with systemic toxicity requiring coverage of both MRSA and streptococci:

• Vancomycin 15-20 mg/kg IV every 8-12 hours PLUS piperacillin-tazobactam 2, 1
• Alternative: Clindamycin 600 mg three times daily as monotherapy if local resistance <10% 1

Treatment Duration

• Standard duration: 5 days if clinical improvement occurs, with extension only if symptoms have not improved 1, 5
• Uncomplicated cellulitis: 5-10 days 1
• Complicated infections: 7-14 days guided by clinical response 1, 5

Risk Factors Mandating MRSA Coverage

MRSA coverage is mandatory when cellulitis is associated with:

• Penetrating trauma 1
• Evidence of MRSA infection elsewhere or prior MRSA colonization 1
• Injection drug use 1
• Purulent drainage 2, 1
• Systemic inflammatory response syndrome (SIRS) 1

Common Pitfalls to Avoid

• Never use β-lactam antibiotics alone when MRSA is suspected or confirmed—they have zero activity against methicillin-resistant organisms 1, 5
• Never use rifampin as monotherapy or add it routinely to other antibiotics for skin infections, as resistance develops rapidly and there is no evidence of benefit 1
• Do not use clindamycin for serious infections if inducible resistance is detected on susceptibility testing, even though it may work for mild infections 1
• TMP-SMX or tetracyclines without a β-lactam will miss streptococcal coverage, which remains the most common cause of typical cellulitis 1
• Failure to drain associated abscesses leads to treatment failure regardless of antibiotic choice 1

Transition to Oral Therapy

Once clinical improvement is demonstrated in hospitalized patients, transition to oral antibiotics:

• TMP-SMX 1-2 double-strength tablets twice daily 5
• Doxycycline 100 mg twice daily 5
• Clindamycin 300-450 mg three times daily (if resistance <10%) 5