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Beta-lactam exposure and safety in intermittent or continuous infusion in critically ill children: an observational monocenter study

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A Correction to this article was published on 19 December 2022

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Abstract

The aim of this study was to assess the pharmacokinetic (PK) exposure and clinical toxicity for three beta-lactams: cefotaxime, piperacillin/tazobactam, and meropenem, depending on two lengths of infusion: continuous and intermittent, in critically ill children. This single center observational prospective study was conducted in a pediatric intensive care unit. All hospitalized children who had one measured plasma concentration of the investigated antibiotics were included. Plasma antibiotic concentrations were interpreted by a pharmacologist, using a Bayesian approach based on previously published population pharmacokinetic models in critically ill children. Exposure was considered optimal, low, or high according to the PK target 100% fT> 4 × MIC and a trough concentration below the toxic concentration (50 mg.L−1 for cefotaxime, 150 mg.L−1 for piperacillin, and 44 mg.L−1 for meropenem). Between May 2019 and January 2020, 80 patients were included and received 106 antibiotic courses: 74 (70%) were administered in intermittent infusion (II) and 32 (30%) in continuous infusion (CI). Compared to II, CI provided more optimal PK exposure (n = 22/32, 69% for CI versus n = 35/74, 47% for II, OR 1.2, 95%CI 1.01–1.5, p = 0.04), less underexposure (n = 4/32, 13% for CI versus n = 36/74, 49% for II, OR 0.7, 95%CI 0.6–0.84, p < 0.001), and more overexposure (n = 6/32, 19% for CI versus n = 3/74, 4% for II, OR 1.2, 95%CI 1.03–1.3, p = 0.01). Five adverse events have been reported during the study period, although none has been attributed to beta-lactam treatment.

Conclusion: CI provided a higher probability to attain an optimal PK target compared to II, but also a higher risk for overexposure. Regular therapeutic drug monitoring is recommended in critically ill children receiving beta-lactams, regardless of the length of infusion.

What is Known:

• Since beta-lactams are time-dependent antibiotics, the probability to attain the pharmacokinetic target is higher with continuous infusion compared to that with intermittent infusion.

• In daily practice, continuous or extended infusions are rarely used despite recent guidelines, and toxicity is hardly reported.

What is New:

• Continuous infusion provided a higher probability to attain an optimal pharmacokinetic target compared to intermittent infusion, but also a higher risk of overexposure.

• Regular therapeutic drug monitoring is recommended in critically ill children receiving beta-lactams, regardless of the length of infusion.

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Change history

Abbreviations

CI:

Continuous infusion

ECOFF:

Epidemiological cutoff

EUCAST:

European Committee on Antimicrobial Susceptibility Testing

HPLC:

High-performance liquid chromatography

II:

Intermittent infusion

MIC:

Minimum inhibitory concentration

PICU:

Pediatric intensive care unit

PK:

Pharmacokinetic

TDM:

Therapeutic drug monitoring

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Acknowledgements

The authors thank the children and their parents who participated in this study, as well as the healthcare providers who participated in the children’s care.

Author information

Authors and Affiliations

  1. Pédiatrie Générale Et Maladies Infectieuses, Hôpital Necker-Enfants Malades, AP-HP, Université de Paris, Paris, France

    Agathe Debray

  2. Hôpital Necker-Enfants Malades, AP-HP, Université de Paris, Pharmacovigilance, Paris, France

    Delphine Callot & Laurent Chouchana

  3. Pharmacologie Et Évaluations Thérapeutiques Chez L’enfant Et La Femme Enceinte, EA7323, Paris, France

    Delphine Callot, Déborah Hirt, Laurent Chouchana, Jean-Marc Tréluyer, Mehdi Oualha & Agathe Béranger

  4. Service de Pharmacologie Clinique, Hôpital Cochin, AP-HP, Paris, France

    Déborah Hirt & Jean-Marc Tréluyer

  5. Laboratoire de Microbiologie, Hôpital Necker-Enfants Malades, AP-HP, Université de Paris, Paris, France

    Emmanuelle Bille

  6. Réanimation Et Surveillance Continue Médico-Chirurgicales Pédiatriques, Hôpital Necker-Enfants Malades, AP-HP, Université de Paris, 149 Rue de Sèvres, 75015, Paris, France

    Sylvain Renolleau, Mehdi Oualha & Agathe Béranger

  7. Unité de Recherche Clinique - Centre d’Investigation Clinique 1419, Hôpital Cochin-Necker, Université de Paris, Inserm, Paris, France

    Jean-Marc Tréluyer

Authors
  1. Agathe Debray
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Contributions

AD conceptualized and designed the study, collected data, carried out the initial analyses, and drafted the initial manuscript. DC, DH, and LC conceptualized and designed the study and collected and interpreted data. EB collected and interpreted data. SR and JMT conceptualized and designed the study and coordinated and supervised data collection. MO conceptualized and designed the study, coordinated and supervised data collection, and contributed to the analysis of the data. AB conceptualized and designed the study, carried out the initial analyses, and drafted the initial manuscript. All authors reviewed and revised critically the manuscript for important intellectual content, approved the final version as submitted, and agree to be accountable for all aspects of the work.

Corresponding author

Correspondence to Agathe Béranger.

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Approval was obtained from the Ethics Committee Comité de protection des personnes Ile-de-France II (CPP2015-01–08-MS4).

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The authors declare no competing interests.

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Communicated by Piet Leroy

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Debray, A., Callot, D., Hirt, D. et al. Beta-lactam exposure and safety in intermittent or continuous infusion in critically ill children: an observational monocenter study. Eur J Pediatr 182, 965–973 (2023). https://doi.org/10.1007/s00431-022-04716-0

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  • DOI: https://doi.org/10.1007/s00431-022-04716-0

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