Daptomycin Plasma and CSF Levels in Patients with Healthcare-Associated Meningitis
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There are currently few data concerning the cerebrospinal fluid (CSF) penetration of daptomycin in patients with healthcare-associated meningitis. This study aims (1) to better characterize the pharmacokinetics of daptomycin in humans during a 7-day intravenous (IV) therapy course, and (2) to study the penetration of daptomycin in the CSF after IV infusion at the dose of 10 mg/kg.
In this prospective observational study, we enrolled nine patients with an implanted external ventricular drainage and a diagnosis of a healthcare-associated meningitis. Daptomycin was administered at 10 mg/kg for a maximum of 7 days. The pharmacokinetic of daptomycin was studied using a two-compartment population/pharmacokinetic (POP/PK) model and by means of a nonlinear mixed effects modeling approach. A large inter-individual variability in plasma area under the curve (Range: 574.7–1366.3 h mg/L), paralleled by high-peak plasma concentration (Cmax) (all values > 60 mg/L), was noted. The inter-individual variability of CSF-AUC although significant (range: 1.17–6.81 h mg/L) was narrower than previously reported and with a late occurrence of CSF-Cmax (range: 6.04–9.54 h). The terminal half-life between plasma and CSF was similar. tmax values in CSF did not show a high inter-individual variability, and the fluctuations of predicted CSF concentrations were minimal. The mean value for daptomycin penetration obtained from our model was 0.45%.
Our POP/PK model was able to describe the pharmacokinetics of daptomycin in both plasma and CSF, showing that daptomycin (up to 7 days at 10 mg/kg) has minimal penetration into central nervous system. Furthermore, the observed variability of AUC, tmax and predicted concentration in CSF was lower than what previously reported in the literature. Based on the present findings, it is unlikely that daptomycin could reach CSF concentrations high enough to have clinical efficacy; this should be tested in future studies.
KeywordsDaptomycin Ventriculitis Meningitis Pharmacokinetics Healthcare-associated meningitis Ventriculitis
Central nervous system
Methicillin-resistant Staphylococcus aureus
Methicillin-resistant Staphylococcus epidermidis
External ventricular drainage
Area under the curve
Center for diseases control
SP and LS contributed to study conception and design. TT, SP and LS acquired the clinical data, AD and TT collected daptomycin CSF and plasma dosage data. All authors helped in interpretation of results. In particular, AP, LG, FC and FC contributed to the POP/PK model elaboration. SP, AD, AP, LG, FC and FC drafted the manuscript. All authors critically revised the manuscript. All the authors approved the manuscript.
Source of support
Compliance with ethical standards
Conflict of interest
All the authors declare that they do not have any Competing Interest.
Ethics approval and consent to participate
This study was approved by the institutional review board (Spedali Civili di Brescia, university of Brescia; IRB1723). Written informed consent was obtained from patients or their legal representatives.
Availability of data and materials
The dataset is available in Github repository, https://github.com/pivadoc/DaptomycinDataset.git.
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