Antibiotics | Cerebrospinal Pharmacokinetic Modeling and Pharmacodynamic Simulation of High-Dose Cefazolin for Methicillin-Susceptible Staphylococcus aureus Meningitis

This study developed a pharmacokinetic model of cefazolin in cerebrospinal fluid and evaluated the therapeutic effectiveness of different dosing regimens for methicillin-susceptible Staphylococcus aureus (MSSA) meningitis through pharmacodynamic simulations, providing an important reference for optimizing antibiotic dosing.

 

Literature Overview
This article, titled 'Cerebrospinal Pharmacokinetic Modeling and Pharmacodynamic Simulation of High-Dose Cefazolin for Meningitis Caused by Methicillin-Susceptible Staphylococcus aureus', published in the journal 'Antibiotics', reviews and summarizes the application of cefazolin in treating central nervous system (CNS) infections, especially meningitis caused by methicillin-susceptible Staphylococcus aureus (MSSA). The study constructs a cefazolin pharmacokinetic model in cerebrospinal fluid (CSF) by integrating existing pharmacokinetic data and evaluates the probability of achieving pharmacodynamic targets with different dosing regimens.

Background Knowledge
Bacterial infections of the central nervous system (CNS) have high mortality rates globally, and MSSA is one of the common causative pathogens. Traditional therapeutic agents such as nafcillin and oxacillin are limited in their use due to adverse side effects and regional unavailability. Cefazolin, a first-generation cephalosporin, exhibits strong antibacterial activity against MSSA but is generally not recommended for CNS infections due to its low CSF penetration. However, recent studies suggest that high-dose cefazolin may be effective in treating meningitis, especially in patients with normal renal function. This study aims to establish a cerebrospinal fluid pharmacokinetic model for cefazolin and optimize therapeutic strategies through simulations of different dosing regimens to enhance efficacy and reduce the risk of neurotoxicity.

 

 

Research Methods and Experiments
The study employed a mixed-model approach, integrating existing pharmacokinetic parameters and physiological factors (e.g., CSF flow rate, CSF/serum concentration ratio) to construct a pharmacokinetic model of cefazolin in cerebrospinal fluid. The model was validated using a sampling importance resampling algorithm, and Monte Carlo simulations were used to assess the probability of achieving pharmacodynamic targets with different dosing regimens. The pharmacodynamic target was defined as 100% time above the minimum inhibitory concentration (T > MIC), and the pharmacokinetic/pharmacodynamic (PK/PD) breakpoint was defined as the highest MIC at which the probability of target attainment in CSF was ≥90%.

Key Conclusions and Perspectives

• For patients with normal renal function (CLcr=90 mL/min), high-dose continuous infusion (6–12 g/day) achieved a PK/PD breakpoint MIC of 0.5–1 µg/mL, effectively inhibiting 90% of MSSA strains (MIC90).
• For patients with impaired renal function (CLcr=30 mL/min), cefazolin dosage needs to be reduced to 4 g/day to avoid excessive drug exposure and potential neurotoxicity.
• Model validation revealed that most observed values fell within the predicted 95% confidence interval, indicating good robustness, although the model carries some uncertainty due to limited CSF sample sizes.
• External data validation demonstrated that simulated CSF concentrations align with previously reported literature, indicating strong predictive capability of the model.

Research Significance and Prospects
This study provides quantitative evidence for the use of cefazolin in CNS infections, supporting the use of high-dose continuous infusion in patients with normal renal function. Future clinical trials are needed to validate the model’s applicability in patients with impaired renal function, and further studies should explore cefazolin’s protein binding rate and toxicity thresholds to optimize therapeutic strategies and reduce neurotoxic risk.

 

 

Conclusion
Cefazolin, despite its traditionally low CSF penetration, is not typically recommended for CNS infections. However, high-dose continuous infusion may increase its CSF concentration and improve therapeutic outcomes due to its strong antibacterial activity against MSSA. The study established a CSF pharmacokinetic model, providing theoretical support for optimizing cefazolin dosing in meningitis treatment. Additionally, the model highlights the importance of dose adjustment according to renal function to prevent neurotoxicity from drug overexposure. These findings offer clinical guidance, particularly when traditional therapies are unavailable or associated with toxic side effects, suggesting cefazolin as a potential alternative. The results also hold implications for personalized therapy and precise dosing strategies, although further clinical validation is necessary to confirm efficacy across varying renal function statuses.

 

Tetsushu Onita, Kazuro Ikawa, Noriyuki Ishihara, Hiroki Tamaki, and Takahisa Yano. Cerebrospinal Pharmacokinetic Modeling and Pharmacodynamic Simulation of High-Dose Cefazolin for Meningitis Caused by Methicillin-Susceptible Staphylococcus aureus. Antibiotics.