What is the preferred treatment between cefazolin and cloxacillin (Cloxacillin is a type of antibiotic, also known as (Dicloxacillin)) for Staphylococcus aureus (MSSA) bacteremia?

Cefazolin vs. Cloxacillin for Staphylococcus aureus Bacteremia

Cefazolin is preferred over cloxacillin for the treatment of methicillin-susceptible Staphylococcus aureus (MSSA) bacteremia due to its comparable efficacy, better safety profile, and lower risk of adverse effects. 1

Efficacy Comparison

• Recent observational data suggest similar efficacy, or even a trend towards superiority of cefazolin over antistaphylococcal penicillins (ASPs) like cloxacillin for MSSA bacteremia 1
• The most recent and highest quality evidence from a 2025 systematic review and meta-analysis showed cefazolin was non-inferior to antistaphylococcal penicillins for mortality outcomes (OR = 0.73,95% CI: 0.62-0.85) 2
• When compared specifically with cloxacillin, cefazolin maintained non-inferiority for mortality (OR = 0.42,95% CI: 0.11-1.58) 2
• A 2018 meta-analysis demonstrated that cefazolin was associated with significant reduction in mortality (OR, 0.69; 95% CI, 0.58 to 0.82) and clinical failure (OR, 0.56; 95% CI, 0.37 to 0.85) compared to ASPs 3

Safety Profile Advantages

• Cefazolin has a preferable safety profile compared to antistaphylococcal penicillins like cloxacillin 1
• Significantly lower rates of nephrotoxicity (OR, 0.36; 95% CI, 0.16 to 0.81) and hepatotoxicity (OR, 0.12; 95% CI, 0.04 to 0.41) have been observed with cefazolin 3
• Cefazolin is associated with lower probability of discontinuation due to adverse effects compared with ASPs (OR, 0.24; 95% CI, 0.12 to 0.48) 3
• The 2025 meta-analysis confirmed these safety advantages with point estimates favoring cefazolin for treatment-related adverse events, nephrotoxicity, and discontinuation due to toxicity 2

Clinical Considerations and Potential Limitations

• There has been concern about decreased efficacy of cefazolin in isolates with the cefazolin inoculum effect (CzIE), where MICs increase to ≥16 μg/mL at high bacterial inocula 1
• An observational study in Argentina showed higher 30-day mortality (39.5% vs 15.2%) in patients with isolates positive for CzIE 1
• However, the clinical significance of CzIE remains uncertain, and recent large-scale observational data support the efficacy of cefazolin despite this theoretical concern 1
• For brain abscesses complicating MSSA bacteremia, nafcillin is preferred over cefazolin due to better blood-brain barrier penetration 1

Treatment Algorithm

1. First-line therapy for MSSA bacteremia: Cefazolin (preferred) 1, 2

   • Typical dosing: 2g IV q8h (adjust for renal function)
   • Benefits: Better safety profile, less nephrotoxicity and hepatotoxicity

2. Alternative therapy: Cloxacillin or other antistaphylococcal penicillins 1

   • Consider when:
     • Patient has specific contraindications to cefazolin
     • CNS infection is present (better CNS penetration) 1

3. Special situations:

   • For brain abscess: Nafcillin preferred over cefazolin 1
   • For patients with severe penicillin allergy (anaphylaxis): Consider vancomycin or daptomycin 1, 4

Ongoing Research

• A French randomized controlled trial (CloCeBa) is currently investigating whether cefazolin is non-inferior to cloxacillin for MSSA bacteremia 1, 5
• This will provide higher quality evidence than the currently available observational studies 5

Conclusion

Based on the most recent and highest quality evidence, cefazolin should be the preferred agent for MSSA bacteremia over cloxacillin due to its comparable efficacy and superior safety profile, with lower rates of adverse effects and treatment discontinuation 1, 3, 2.