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Defining Safe and Effective Cefazolin Dosing Regimens for MSSA Infections in the CNS: Leveraging Sparse Real-World
Samuel Dubinsky1, Mark McIntyre2,3, Min-Soo Kim4
1Department of Critical Care, Faculty of Medicine, Dalhousie University, Halifax, NS, Canada. sam.dubinsky@nshealth.ca.
Background And Objective:
Infections in the central nervous system (CNS) are serious and carry a significant risk of morbidity and mortality. Though commonly used as prophylaxis for neurosurgical interventions, cefazolin as a treatment for CNS infections due to methicillin-susceptible Staphylococcus aureus (MSSA) has been debated owing to the perceived inability to achieve adequate concentrations at the site of infection. The objective of the current study was to evaluate the dose-exposure-response relationship of cefazolin in the CNS.
Methods:
To leverage sparse data of cefazolin in the cerebrospinal fluid (CSF) and derive an understanding of the dose-exposure-response profile in the CNS, a physiologically-based pharmacokinetic (PBPK) model was created in PK-Sim. Simulations were performed using standard cefazolin dosing of 2000 mg every 8 h and alternative regimens to maximize the probability of target attainment (PTA). The pharmacodynamic target used was 100% fT > MIC (100% of free drug concentrations above the minimum inhibitory concentration). Furthermore, a neurotoxicity threshold of ≥ 300 mg/L and ≥ 30 mg/L for trough concentrations was set as the safety indicator in plasma and CSF, respectively.
Results:
The cefazolin CSF-PBPK model was successfully validated such that predicted CSF:plasma ratios were within a 1.5-fold error compared with the observed values. In addition, the median predicted CSF:epidemiological cut-off (ECOFF) concentration ratio was 2.52, compared with an observed value of 2.8. In silico simulations demonstrate that intermittent doses of 2000 mg every 6 h or a continuous infusion of 8-10 g/day may be required to ensure 90% PTA for MSSA to a MIC ≤ 2 mg/L. Predicted plasma and CSF concentrations were well below concentrations associated with neurotoxicity.
Conclusions:
This study is the first to use sparse observed CNS data to develop a mechanistic model to describe the pharmacokinetics of cefazolin in the CSF. This work supports existing research on the viability of cefazolin as a therapeutic alternative for CNS infections attributed to MSSA and can be used for future clinical trial planning.
Insights
Cefazolin may effectively treat central nervous system (CNS) infections caused by methicillin-susceptible Staphylococcus aureus (MSSA). Higher doses or continuous infusion may be needed to achieve adequate drug concentrations in the CNS.
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.
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