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The pharmacokinetics of meropenem and piperacillin-tazobactam during sustained low efficiency haemodiafiltration (SLED-HDF)

  • Pharmacokinetics and Disposition
  • Published:
European Journal of Clinical Pharmacology Aims and scope Submit manuscript

Abstract

Objective

We analysed the pharmacokinetics of meropenem and piperacillin-tazobactam in patients undergoing a standardised session of sustained low efficiency haemodiafiltration (SLED-HDF) to inform the dosing of these drugs in an acute setting.

Participants

Six stable patients with end-stage kidney disease.

Methods

An open-label pilot pharmacokinetic study of meropenem and piperacillin-tazobactam. SLED-HDF was undertaken for 4 h. Plasma drug concentrations were measured pre- and post-filter and in the effluent at multiple time points. The pharmacokinetic data was analysed using non-compartmental methods. The fraction of time that individual plasma concentration profiles were predicted to remain above the MIC break-points for commonly isolated gram-negative pathogens during a prolonged SLED-HDF session was assessed using two targets; fT > MIC (fraction of time above the MIC) and the more aggressive fT > 4 × MIC (fraction of time above 4 × MIC).

Results

Meropenem total and SLED-HDF clearance ranged from 141 to 180 mL/min and 126–205 mL/min, respectively. Piperacillin total and SLED-HDF clearance values ranged from 131 to 252 mL/min and 135–162 mL/min, respectively. Our results suggest that prolonged SLED-HDF (12 h) will only maintain a sufficient meropenem and piperacillin-tazobactam plasma concentration to achieve a target of fT > MIC for gram-negative pathogens (MIC 2 mg/L-meropenem, 8 mg/L-piperacillin-tazobactam) for less than 40% of the time. Plasma concentrations would be inadequate to achieve the more aggressive target of 100 % fT > 4xMIC target recommended for critically unwell patients.

Conclusions

The pharmacokinetic data obtained from this pilot study demonstrate significant quantities of meropenem and piperacillin are removed during a SLED-HDF session. This may lead to subtherapeutic concentrations of piperacillin and meropenem over the duration of HDF session.

Trial registration

Australasian Clinical Trials Registry Network (ACTRN12616000078459)

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Acknowledgements

The meropenem and piperacillin analyses were performed in the Burns Trauma & Critical Care Research Centre, University of Queensland, Australia. Dr. Luke Wilson provided assistance with Body Composition Measurements (BCM) and sample handling. The dialysis staff Dunedin Hospital, provided the SLED-HDF therapy. JR would like to acknowledge funding for a NHMRC Centre of Research Excellence (APP1099452) and a Practitioner Fellowship (APP1117065).

Funding

This study was financially funded by a Laurenson Award, Otago Medical Research Foundation, Dunedin, New Zealand.

Author information

Authors and Affiliations

  1. Department of Nephrology, Southern District Health Board, Dunedin, New Zealand

    Sine Donnellan, John B. W. Schollum, Tracey L. Putt & Robert J. Walker

  2. Department of Medicine, Dunedin School of Medicine, University of Otago, PO Box 56, Dunedin, 9054, New Zealand

    Sine Donnellan, John B. W. Schollum, Tracey L. Putt & Robert J. Walker

  3. School of Pharmacy, University of Otago, Dunedin, New Zealand

    Daniel F. B. Wright & Stephen B. Duffull

  4. University of Queensland Centre for Clinical Research, Faculty of Medicine & Centre for Translational Anti-infective Pharmacodynamics, School of Pharmacy, The University of Queensland, Brisbane, Australia

    Jason A. Roberts

  5. University of Queensland Centre for Clinical Research, The University of Queensland, Brisbane, Australia

    Steven C. Wallis

Authors
  1. Sine Donnellan
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  2. Daniel F. B. Wright
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  3. Jason A. Roberts
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  6. Tracey L. Putt
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  7. Steven C. Wallis
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Contributions

Robert Walker, John Schollum, Tracey Putt, Dan Wright, and Stephen Duffull contributed to the initial concepts and design of the study. Sine Donnellan undertook the clinical studies and preparation of samples. Jason Roberts and Steve Wallis undertook the analyses of the meropenem and piperacillin concentrations. Dan Wright, Stephen Duffull, Sine Donnellan, and Jason Roberts undertook the pharmacokinetic analyses. All authors (RW, JS, TP, SDo, SDu, JR, SW) contributed to the drafts and final manuscript.

Corresponding author

Correspondence to Robert J. Walker.

Ethics declarations

Declaration

This study was approved by the Southern Health and Disability Ethics Committee (16/STH/9). All participants provided written informed consent. All procedures performed in this study involving human participants were in accordance with the ethical standards of the Southern Health and Disability Ethics Committee (16/STH/9) and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

The Ethics committee did not approve the storage of the raw data in a public repository. However, full de-identified participant data are available from the corresponding author on reasonable request and approval from a suitable ethics committee.

Conflict of interest

The authors declare that they have no conflicts of interest.

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Donnellan, S., Wright, D.F.B., Roberts, J.A. et al. The pharmacokinetics of meropenem and piperacillin-tazobactam during sustained low efficiency haemodiafiltration (SLED-HDF). Eur J Clin Pharmacol 76, 239–247 (2020). https://doi.org/10.1007/s00228-019-02792-0

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