Recommended Antibiotics for MSSA Infections
Proven MSSA Infections: Preferred Agents
For proven methicillin-sensitive Staphylococcus aureus infections, oxacillin, nafcillin, or cefazolin are the preferred antibiotics, with antistaphylococcal penicillins (oxacillin/nafcillin) being first-line for serious infections like bacteremia and endocarditis. 1
Intravenous Therapy for Serious Infections
Antistaphylococcal penicillins remain the gold standard:
- Nafcillin or oxacillin 2 g IV every 4 hours for bacteremia, endocarditis, and other invasive infections 2, 3, 4
- Cefazolin 2 g IV every 8 hours is an acceptable alternative, particularly for patients with non-severe penicillin allergies (excluding immediate hypersensitivity reactions) 1, 2
- Cefazolin demonstrated equivalent outcomes to antistaphylococcal penicillins in MSSA bacteremia, regardless of oxacillin MIC values (≥1 versus <1 μg/mL) 5
Oral Therapy for Less Severe Infections
For outpatient or step-down therapy:
- Dicloxacillin 500 mg orally four times daily is the oral agent of choice 6
- Cephalexin 500 mg orally four times daily for penicillin-allergic patients (except immediate hypersensitivity) 6
- Clindamycin 300-450 mg orally three times daily for true penicillin allergy or skin/soft tissue infections 6, 2
Empiric Coverage When MSSA is Suspected
When empiric therapy must cover MSSA (but MRSA coverage is not indicated), use one of the following broad-spectrum agents that provide adequate MSSA activity: 1
- Piperacillin-tazobactam 4.5 g IV every 6 hours
- Cefepime 2 g IV every 8 hours
- Levofloxacin 750 mg IV daily
- Imipenem 500 mg IV every 6 hours
- Meropenem 1 g IV every 8 hours
These agents are appropriate for empiric hospital-acquired pneumonia when MRSA risk factors are absent 1
Critical Clinical Considerations
When to Switch from Empiric to Targeted Therapy
Once MSSA is confirmed by culture, immediately narrow therapy to oxacillin, nafcillin, or cefazolin rather than continuing broad-spectrum agents 1. This reduces the risk of Clostridioides difficile infection, antibiotic resistance, and adverse drug effects while maintaining optimal efficacy 1
Penicillin Allergy Management
- For non-immediate hypersensitivity: First-generation cephalosporins (cefazolin, cephalexin) are safe and effective 6, 2
- For immediate hypersensitivity (urticaria, angioedema, bronchospasm, anaphylaxis): Cephalosporins are contraindicated; use clindamycin, vancomycin, or daptomycin instead 2
Agents to Avoid or Use with Caution
Once-daily regimens (ceftriaxone, daptomycin) lack sufficient evidence for MSSA bacteremia and should not be used as first-line therapy 7. While daptomycin showed non-inferior outcomes in S. aureus bacteremia trials (44% success rate), it was studied at 6 mg/kg dosing and is not FDA-approved as first-line for MSSA when better options exist 8, 7
Fluoroquinolones as monotherapy should be avoided due to rapid resistance development, though levofloxacin may be used empirically in specific hospital-acquired pneumonia scenarios 1, 4
Treatment Duration
- Uncomplicated skin/soft tissue infections: 5-10 days 6
- Complicated bacteremia: Typically 14 days minimum, depending on source control and clinical response 8
- Endocarditis: 4-6 weeks of IV therapy 8
Common Pitfalls to Avoid
- Never continue broad-spectrum empiric therapy once MSSA is confirmed—this increases toxicity and resistance without improving outcomes 1
- Do not use vancomycin for proven MSSA infections when beta-lactams can be used; beta-lactams have superior efficacy 2, 3
- Ensure adequate source control (drainage of abscesses, removal of infected devices) as antibiotics alone will fail without it 8
- Verify local resistance patterns before using clindamycin, as resistance rates >10% make it unreliable 2