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

<b>Background:</b> Cefazolin is being increasingly used to treat central nervous system infections caused by methicillin-susceptible <i>Staphylococcus aureus</i> (MSSA) to mitigate the side effects of existing anti-Staphylococcal drugs. This study aims to develop a cerebrospinal pharmacokinetic (PK) model to predict the cefazolin concentration in cerebrospinal fluid (CSF) and to individualize the dosing regimen for MSSA meningitis. <b>Methods:</b> A cerebrospinal PK model was developed based on the existing literature and used to estimate the probability of attaining PK/ pharmacodynamic (PD) targets. These targets were set as 100% time above the minimum inhibitory concentration (T > MIC) in CSF. The cerebrospinal PK/PD breakpoint was defined as the highest MIC at which target attainment probability in CSF was ≥90%. The mean CSF/serum ratio estimated from the literature was 0.0525 after a dose of 1-3 g (sampling time: 1-9 h after dose) in adult patients with suspected meningitis. This ratio was incorporated into this PK model based on a hybrid approach. <b>Results:</b> For patients with creatinine clearance (CL_cr) = 90 mL/min, the cerebrospinal PK/PD breakpoint MICs of continuous infusion regimens (6-12 g/day) reached 0.5 µg/mL, which can inhibit the growth of 90% of the MSSA population (MIC₉₀). Furthermore, for patients with renal dysfunction (CL_cr = 30 mL/min), a dose reduction (4 g/day) may be required to avoid excessive drug exposure. <b>Conclusions:</b> High-dose continuous infusion of cefazolin may be appropriate for MSSA meningitis in patients with normal renal function, while dose adjustments are needed for those with renal impairment.