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Daptomycin Plasma and CSF Levels in Patients with Healthcare-Associated Meningitis

  • S. Piva
  • Antonello Di Paolo
  • Laura Galeotti
  • Francesco Ceccherini
  • Francesco Cordoni
  • Liana Signorini
  • Tommaso Togni
  • Amedeo De Nicolò
  • Frank A. Rasulo
  • Nazzareno Fagoni
  • N. Latronico
  • Antonio D’Avolio
Original Article
  • 50 Downloads

Abstract

Background

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.

Results

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%.

Conclusions

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.

Keywords

Daptomycin Ventriculitis Meningitis Pharmacokinetics Healthcare-associated meningitis Ventriculitis 

Abbreviations

CSF

Cerebrospinal fluid

CNS

Central nervous system

MRSA

Methicillin-resistant Staphylococcus aureus

MRSE

Methicillin-resistant Staphylococcus epidermidis

G+

Gram-positive

EVD

External ventricular drainage

POP/PK

Population/pharmacokinetic

AUC

Area under the curve

CDC

Center for diseases control

CPK

Creatine phosphokinase

CRCL

Creatinine clearance

SD

Standard deviation

Notes

Author contribution

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

None.

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.

Supplementary material

12028_2018_657_MOESM1_ESM.docx (679 kb)
Supplementary material 1 (DOCX 678 kb)

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Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature and Neurocritical Care Society 2019

Authors and Affiliations

  • S. Piva
    • 1
    • 6
  • Antonello Di Paolo
    • 2
  • Laura Galeotti
    • 3
  • Francesco Ceccherini
    • 3
  • Francesco Cordoni
    • 3
  • Liana Signorini
    • 4
  • Tommaso Togni
    • 1
  • Amedeo De Nicolò
    • 5
  • Frank A. Rasulo
    • 1
    • 6
  • Nazzareno Fagoni
    • 1
  • N. Latronico
    • 1
    • 6
  • Antonio D’Avolio
    • 5
  1. 1.Department of Anesthesia, Critical Care and EmergencySpedali Civili University HospitalBresciaItaly
  2. 2.Department of Clinical and Experimental Medicine, Section of PharmacologyUniversity of PisaPisaItaly
  3. 3.Phymtech Srl (Physical and Mathematical Technologies)PisaItaly
  4. 4.Second Division of Clinical Infectious Diseases, Department of Infectious DiseasesSpedali Civili University HospitalBresciaItaly
  5. 5.Unit of Infectious Diseases, Department of Medical Sciences, Amedeo di Savoia HospitalUniversity of TurinTurinItaly
  6. 6.Department of Medical and Surgical Specialties, Radiological Sciences and Public HealthUniversity of BresciaBresciaItaly

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