Abstract
The aim of this study was to describe the pharmacokinetics of ceftolozane-tazobactam in plasma and cerebrospinal fluid (CSF) of infected critically ill patients. In a prospective observational study, critically ill patients (≥18 years) with an indwelling external ventricular drain received a single intravenous dose of 3.0 g ceftolozane-tazobactam. Serial plasma and CSF samples were collected for measurement of unbound ceftolozane and tazobactam concentration by liquid chromatography. Unbound concentration-time data were modeled in R using Pmetrics. Dosing simulations were performed using the final model. A three-compartment model adequately described the data from 10 patients. For ceftolozane, the median (interquartile range [IQR]) area under the unbound concentration-time curve from time zero to infinity (fAUC0-inf) in the CSF and plasma were 30 (19 to 128) h·mg/liter and 323 (183 to 414) h·mg/liter, respectively. For tazobactam, these values were 5.6 (2 to 24) h·mg/liter and 52 (36 to 80) h·mg/liter, respectively. Mean ± standard deviation (SD) CSF penetration ratios were 0.2 ± 0.2 and 0.2 ± 0.26 for ceftolozane and tazobactam, respectively. With the regimen of 3.0 g every 8 h, a probability of target attainment (PTA) of ≥0.9 for 40% fT>MIC in the CSF was possible only when MICs were ≤0.25 mg/liter. The CSF cumulative fractional response for Pseudomonas aeruginosa-susceptible MIC distribution was 73%. The tazobactam PTA for the minimal suggested exposure of 20% fT>1 mg/liter was 12%. The current maximal dose of ceftolozane-tazobactam (3.0 g every 8 h) does not provide adequate CSF exposure for treatment of Gram-negative meningitis or ventriculitis unless the MIC for the causative pathogen is very low (≤0.25 mg/liter).
Highlights
The aim of this study was to describe the pharmacokinetics of ceftolozanetazobactam in plasma and cerebrospinal fluid (CSF) of infected critically ill patients
This observation is not unexpected, given the physicochemical properties of both of these drug molecules and that lipid solubility is a major determinant of antibiotic penetration across the blood-brain barrier (BBB) via passive diffusion [10, 11]
It is worth noting that in the present study, half of the participants had presumed or confirmed ventriculitis; this is distinct from meningitis patients, where CSF concentrations of beta-lactam antibiotics are more likely to be increased because inflamed meninges open the tight junctions, which likely enable increased passive drug diffusion into CSF [12]
Summary
The aim of this study was to describe the pharmacokinetics of ceftolozanetazobactam in plasma and cerebrospinal fluid (CSF) of infected critically ill patients. The current maximal dose of ceftolozanetazobactam (3.0 g every 8 h) does not provide adequate CSF exposure for treatment of Gram-negative meningitis or ventriculitis unless the MIC for the causative pathogen is very low (Յ0.25 mg/liter). Ceftolozane-tazobactam is a relatively novel antipseudomonal beta-lactam antibiotic with activity against Gram-negative bacteria, including multidrug-resistant P. aeruginosa [4, 5] It is approved for the treatment of complicated urinary tract infections, complicated intra-abdominal infections, hospital-acquired bacterial pneumonia, and ventilator-associated pneumonia [6]. The aim of this study was to describe the plasma and CSF population pharmacokinetics of ceftolozane and tazobactam and evaluate the adequacy of CSF exposure from intravenous dosing regimens (3 g every 8 h [q8h], 3-g loading dose plus 9-g continuous infusion) in the treatment of critically ill patients with an indwelling external ventricular drain (EVD)
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