Defining Safe and Effective Cefazolin Dosing Regimens for MSSA Infections in the CNS: Leveraging Sparse Real-World...

Area of Science:

• Pharmacokinetics and Pharmacodynamics
• Infectious Diseases
• Neurosurgery

Background:

• Central nervous system (CNS) infections pose significant risks.
• Cefazolin is used for surgical prophylaxis but its therapeutic use for CNS infections is debated.
• Achieving adequate cefazolin concentrations in the CNS is a key concern.

Purpose of the Study:

• To evaluate the dose-exposure-response relationship of cefazolin in the CNS.
• To develop a physiologically-based pharmacokinetic (PBPK) model for cefazolin in the CNS.
• To determine optimal dosing regimens for treating CNS infections.

Main Methods:

• A PBPK model was developed using PK-Sim and sparse cerebrospinal fluid (CSF) data.
• Simulations explored standard and alternative cefazolin dosing regimens.
• Pharmacodynamic targets included 100% time above minimum inhibitory concentration (MIC) and neurotoxicity thresholds.

Main Results:

• The cefazolin CSF-PBPK model was successfully validated against observed data.
• Simulations suggest higher intermittent doses (2000 mg q6h) or continuous infusion (8-10 g/day) are needed for 90% target attainment against MSSA with MIC ≤ 2 mg/L.
• Predicted cefazolin concentrations remained below neurotoxicity thresholds.

Conclusions:

• This study presents the first mechanistic model for cefazolin pharmacokinetics in CSF.
• The findings support cefazolin's potential as a treatment for CNS infections caused by MSSA.
• The model can aid in planning future clinical trials for cefazolin in CNS infections.