What is the preferred antibiotic for treating Methicillin-Susceptible Staphylococcus aureus (MSSA) bacteremia, cefazolin or cloxacillin?

Cefazolin vs Cloxacillin for MSSA Bacteremia

Cefazolin is the preferred agent for most patients with MSSA bacteremia, demonstrating superior or equivalent efficacy to antistaphylococcal penicillins (ASPs) like cloxacillin with a significantly better safety profile. 1

Primary Recommendation

Use cefazolin as first-line therapy for MSSA bacteremia in most clinical scenarios. 1 While guidelines traditionally list oxacillin, nafcillin, or cefazolin as equivalent preferred agents 2, the most recent high-quality meta-analysis from 2018 demonstrates that cefazolin is associated with:

• Lower mortality compared to ASPs (OR 0.69,95% CI 0.58-0.82) 1
• Lower clinical failure rates (OR 0.56,95% CI 0.37-0.85) 1
• No difference in bacteremia recurrence (OR 1.12,95% CI 0.94-1.34) 1
• Significantly fewer adverse effects, including nephrotoxicity (OR 0.36) and hepatotoxicity (OR 0.12) 1
• Lower discontinuation rates due to adverse effects (OR 0.24) 1

Clinical Algorithm for Agent Selection

Use Cefazolin When:

• Uncomplicated MSSA bacteremia without CNS involvement 2, 1
• Patients at higher risk for drug toxicity (elderly, renal impairment, multiple comorbidities) 1
• Endocarditis without brain abscess 2, 1
• Any MSSA bacteremia where safety profile is a concern 1

Use Cloxacillin/Nafcillin When:

• Brain abscess or CNS infection complicating MSSA bacteremia, as nafcillin has superior blood-brain barrier penetration compared to cefazolin 2
• Meningitis with MSSA 2

Either Agent is Acceptable:

• Right-sided endocarditis 2, 1
• Left-sided endocarditis without CNS complications 2, 1

Addressing the Cefazolin Inoculum Effect (CzIE) Controversy

The cefazolin inoculum effect should not deter use of cefazolin in clinical practice. 2 While some in vitro studies show increased MICs with higher inocula, recent evidence demonstrates:

• Observational data suggest similar or superior efficacy of cefazolin compared to ASPs in real-world practice 2
• Oxacillin MIC variations (≥1 vs <1 μg/mL) do not affect treatment outcomes with either cefazolin or ASPs 3
• The preferable safety profile of cefazolin outweighs theoretical concerns about the inoculum effect 2
• One Argentine study showed higher mortality with CzIE-positive isolates, but this was in hospitals without antimicrobial stewardship programs, limiting generalizability 2

Dosing Considerations

• Cefazolin: 2 grams IV every 8 hours for serious infections 2
• Cloxacillin: 2 grams IV every 4-6 hours 4
• Duration: Minimum 14 days for uncomplicated bacteremia; 4-6 weeks for complicated infections or endocarditis 2, 5

Critical Pitfalls to Avoid

• Do not use vancomycin for MSSA when beta-lactams can be used, as beta-lactams demonstrate superior efficacy 2, 6
• Avoid gentamicin for MSSA bacteremia—it provides no benefit and increases nephrotoxicity risk 2, 5
• Do not continue broad-spectrum empiric antibiotics (piperacillin-tazobactam, carbapenems) once MSSA is confirmed; narrow to cefazolin or ASP 5, 6
• Switch from cefazolin to nafcillin immediately if CNS involvement is identified 2
• Do not use second or third-generation cephalosporins (cefuroxime, ceftriaxone, cefotaxime) for definitive MSSA therapy—they are associated with higher mortality 4

Special Populations

Penicillin Allergy:

• Non-anaphylactic allergy: Cefazolin is safe and preferred 5
• Anaphylactic/immediate hypersensitivity: Use vancomycin or daptomycin; cephalosporins are contraindicated 5

Polymicrobial Infections:

• If MSSA plus gram-negatives/anaerobes, use cefazolin for MSSA plus appropriate gram-negative coverage (e.g., cefepime for Pseudomonas) 6
• Do not rely on broad-spectrum agents alone for optimal MSSA coverage 6