Population pharmacokinetic modeling of ceftriaxone in cerebrospinal fluid in children: should we be using once- or twice-daily dosing for meningitis?

Abstract

Guidelines for bacterial meningitis in children recommend intravenous ceftriaxone 50 mg/kg (max 2 g) twice daily (BD) or 100 mg/kg (max 4 g) once daily (OD), leaving the decision regarding the dose frequency to the prescriber. We investigated the cerebrospinal fluid (CSF) penetration of ceftriaxone to evaluate whether one dosing regimen is superior. Unbound ceftriaxone concentrations were measured in serum and CSF samples from children aged 0-18 years treated with ceftriaxone if there was a sample remaining after clinical tests were performed. A serum-CSF population pharmacokinetic model was developed using non-linear mixed-effects modeling. The once- and twice-daily dosing regimens were simulated, and the probability of target attainment (PTA) was determined for maintaining a CSF concentration above a minimum inhibitory concentration (MIC) of 1 mg/L for common meningitis pathogens and 4 mg/L for Staphylococcus aureus for 100% of the dosing interval. Sixteen serum and 87 CSF samples were collected from 98 children (age range 0.1-18.5 years). The final two-compartment serum-CSF model included a renal maturation function with weight scaling on clearance and volume of distribution. The estimated serum:CSF uptake was 20.1%. For MIC 1 mg/L, the 24 h PTA was higher for OD (88%) compared with BD (53%) dosing, although both achieved a 100% PTA at steady state. For S. aureus (MIC 4 mg/L), neither dosing regimen was sufficient. Our findings support the use of a 100 mg/kg once daily regimen for empirical treatment of bacterial meningitis due to earlier achievement of the pharmacodynamic target. Neither dosing regimen was adequate for S. aureus meningitis.

Keywords: cephalosporins; cerebrospinal fluid penetration; dosing; meningitis; pediatrics; population pharmacokinetics.

Fig 1

CSF ceftriaxone concentrations versus time plots in simulated patients. The middle line indicates the median CSF ceftriaxone concentration of simulated patients, and the shaded area indicates the CSF ceftriaxone concentration in 95% of simulated patients.

Fig 2

Probability of target attainment (100%T > MIC) in cerebrospinal fluid with increasing target MICs, which is shown in the first 2.5–24 h, at 72 to 96 h, and 168 to 192 h after the start of treatment.