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Population pharmacokinetics and probability of target attainment of meropenem in critically ill patients

  • Pharmacokinetics and Disposition
  • Published:
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Abstract

Purpose

Patients admitted to intensive care unit (ICU) with Klebsiella pneumoniae infections are characterized by high mortality. The aims of the present study were to investigate the population pharmacokinetics parameters and to assess the probability of target attainment of meropenem in critically ill patients to provide information for more effective regimens.

Methods

Twenty-seven consecutive patients were included in the study. Meropenem was administered as 3-h intravenous (i.v.) infusions at doses of 1–2 g every 8 or 12 h. Meropenem plasma concentrations were measured by a high-performance liquid chromatography (HPLC) method, and a population pharmacokinetics analysis was performed using NONMEM software. Meropenem plasma disposition was simulated for extended (3 h; 5 h) or continuous i.v. infusions, and the following parameters were calculated: time during which free drug concentrations were above minimum inhibitory concentration (MIC) (fT > MIC), free minimum plasma concentrations above 4× MIC (fCmin > 4× MIC), probability of target attainment (PTA), and cumulative fraction of response (CFR).

Results

Gender and severity of sepsis affected meropenem clearance, whose typical population values ranged from 6.22 up to 12.04 L/h (mean ± standard deviation (SD) value, 9.38 ± 4.47 L/h). Mean C min value was 7.90 ± 7.91 mg/L, suggesting a high interindividual variability. The simulation confirmed that 88 and 97.5 % of patients achieved effective C min > 4× MIC values after 3- and 5-h i.v. infusions of meropenem 2 g × 3/day, respectively. On the contrary, the same total daily doses reached the target C min > 4× MIC values in 100 % of patients when administered as continuous i.v. infusions.

Conclusions

Several factors may influence meropenem pharmacokinetics in ICU patients. Continuous i.v. infusions of meropenem seem to be more effective than standard regimens to achieve optimal therapeutic targets.

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Acknowledgments

The authors should thank the patients, their relatives, and nurse staff for their invaluable support in this study.

Author’s contribution

Authors

Conception and design of study

Acquisition of data: laboratory or clinical

Analysis of data

Drafting of article and/or critical revision

Final approval of manuscript

Francesca Mattioli

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Carmen Fucile

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Valerio Del Bono

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Valeria Marini

 

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Andrea Parisini

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Alexandre Molin

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Maria Laura Zuccoli

 

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Giulia Milano

 

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Romano Danesi

   

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Anna Marchese

 

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Marialuisa Polillo

  

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Claudio Viscoli

   

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Paolo Pelosi

   

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Antonietta Martelli

   

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Antonello Di Paolo

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Author information

Authors and Affiliations

  1. Department of Internal Medicine, Clinical Pharmacology and Toxicology Unit, University of Genoa, Viale Benedetto XV, n. 2, 16132, Genoa, Italy

    Francesca Mattioli, Carmen Fucile, Valeria Marini, Maria Laura Zuccoli, Giulia Milano & Antonietta Martelli

  2. Infectious Diseases Clinics, IRCCS A.O.U San Martino-IST, University of Genoa, Largo R. Benzi, n. 10, 16132, Genoa, Italy

    Valerio Del Bono, Andrea Parisini & Claudio Viscoli

  3. Anesthesia and Intensive Care, Department Surgical Sciences and Integrated Diagnostics, IRCCS A.O.U San Martino-IST, University of Genoa, Largo R. Benzi, n. 10, 16132, Genoa, Italy

    Alexandre Molin & Paolo Pelosi

  4. Department of Clinical and Experimental Medicine, University of Pisa, Via Savi, n.10, 56126, Pisa, Italy

    Romano Danesi, Marialuisa Polillo & Antonello Di Paolo

  5. Section of Microbiology-DISC, University of Genoa, Largo R. Benzi, n. 10, 16132, Genoa, Italy

    Anna Marchese

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  1. Francesca Mattioli
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Corresponding author

Correspondence to Francesca Mattioli.

Ethics declarations

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. Informed consent was obtained from all individual participants included in the study.

Disclosure

The study did not provide any source of funding by sponsor.

Conflict of interest

Antonello Di Paolo is a board member for Novartis Pharma Spa. The other authors have none to declare.

Headings

- Meropenem pharmacokinetics is highly variable in ICU patients with severe infections, and some patients do not achieve effective meropenem plasma concentrations.

- The severity of infection does influence the pharmacokinetics of meropenem.

- Meropenem efficacy could be increased by the adoption of continuous infusions.

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Mattioli, F., Fucile, C., Del Bono, V. et al. Population pharmacokinetics and probability of target attainment of meropenem in critically ill patients. Eur J Clin Pharmacol 72, 839–848 (2016). https://doi.org/10.1007/s00228-016-2053-x

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  • DOI: https://doi.org/10.1007/s00228-016-2053-x

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