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

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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.

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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

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Funding

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Author information

Authors and Affiliations

  1. Department of Anesthesia, Critical Care and Emergency, Spedali Civili University Hospital, Piazzale Spedali Civili di Brescia 1, Brescia, Italy

    S. Piva, Tommaso Togni, Frank A. Rasulo, Nazzareno Fagoni & N. Latronico

  2. Department of Clinical and Experimental Medicine, Section of Pharmacology, University of Pisa, Via Roma, 67, Pisa, Italy

    Antonello Di Paolo

  3. Phymtech Srl (Physical and Mathematical Technologies), Via Giuntini 63, Navacchio di Cascina, Pisa, Italy

    Laura Galeotti, Francesco Ceccherini & Francesco Cordoni

  4. Second Division of Clinical Infectious Diseases, Department of Infectious Diseases, Spedali Civili University Hospital, Piazzale Spedali Civili di Brescia, Brescia, Italy

    Liana Signorini

  5. Unit of Infectious Diseases, Department of Medical Sciences, Amedeo di Savoia Hospital, University of Turin, Turin, Italy

    Amedeo De Nicolò & Antonio D’Avolio

  6. Department of Medical and Surgical Specialties, Radiological Sciences and Public Health, University of Brescia, Piazza del Mercato, 15, Brescia, Italy

    S. Piva, Frank A. Rasulo & N. Latronico

Authors
  1. S. Piva
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  2. Antonello Di Paolo
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  3. Laura Galeotti
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  12. Antonio D’Avolio
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Contributions

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.

Corresponding author

Correspondence to S. Piva.

Ethics declarations

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.

Additional information

The present work was held at Department of Anesthesia, Critical Care and Emergency, Spedali Civili University Hospital.

Electronic supplementary material

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Supplementary material 1 (DOCX 678 kb)

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Piva, S., Di Paolo, A., Galeotti, L. et al. Daptomycin Plasma and CSF Levels in Patients with Healthcare-Associated Meningitis. Neurocrit Care 31, 116–124 (2019). https://doi.org/10.1007/s12028-018-0657-y

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  • DOI: https://doi.org/10.1007/s12028-018-0657-y

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