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Once-daily 1 g ceftriaxone optimizes exposure in patients with septic shock and hypoalbuminemia receiving continuous veno-venous hemodiafiltration

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

Abstract

Purpose

Ceftriaxone total and unbound pharmacokinetics (PK) can be altered in critically ill patients with septic shock and hypoalbuminemia receiving continuous veno-venous hemodiafiltration (CVVHDF). The objective of this study was to determine the dosing strategy of ceftriaxone that maximizes the probability of maintaining the concentration above the MIC of the susceptible bacteria (≤2 mg/L by the EUCAST) for a 100% of the dosing interval (100% ƒuT>MIC).

Methods

In a prospective PK study in the intensive care units of two tertiary Spanish hospitals, six timed blood samples were collected per patient; for each sample, ceftriaxone total and unbound concentrations were measured using a liquid chromatography coupled to tandem mass spectrometry method. Population PK analysis and Monte-Carlo simulations were performed using NONMEMv.7.3®.

Results

We enrolled 8 critically ill patients that met the inclusion criteria (47 blood samples). Median age (range) was 70 years (47-85), weight 72.5 kg (40-95), albumin concentration 24.2 g/L (22-34), APACHE II score at admission 26 (17-36), and SOFA score on the day of study 12 (9-15). The unbound fraction (ƒu) of ceftriaxone was 44%, and total CL was 1.27 L/h, 25-30% higher than the CL reported in septic critically ill patients not receiving renal replacement therapies, and dependent on albumin concentration and weight. Despite this increment in ƒu and CL, Monte-Carlo simulations showed that a dose of 1 g once-daily ceftriaxone is sufficient to achieve a 100% ƒuT>MIC for MICs ≤2 mg/L for any range of weight and albumin concentration.

Conclusion

Once-daily 1 g ceftriaxone provides optimal exposure in critically ill patients with septic shock and hypoalbuminemia receiving CVVHDF.

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Funding

This work has been supported by a grant from the Spanish Ministry of Health, Social Policies and Equality (Ministerio de Sanidad, Servicios Sociales y Igualdad), Government of Spain, project grant number EC11-159. Marta Ulldemolins has been supported in part by this project grant.

Author information

Author notes

  1. Marta Ulldemolins, Carla Bastida, Ignacio Martín-Loeches and Dolors Soy contributed equally to this work.

Authors and Affiliations

  1. Infectious Diseases – Internal Medicine Departments, Bellvitge University Hospital, University of Barcelona, L’Hopspitalet de Llobregat, Spain

    Marta Ulldemolins

  2. Pharmacy Department, Division of Medicines, Hospital Clinic de Barcelona, Barcelona, Spain

    Carla Bastida & Dolors Soy

  3. Department of Nursing, School of Medicine and Health Sciences, Universitat Internacional de Catalunya, Barcelona, Spain

    Mireia Llauradó-Serra

  4. Service of Clinical Pharmacology, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland

    Chantal Csajka

  5. School of Pharmaceutical Sciences, University of Geneva, University of Lausanne, Geneva, Switzerland

    Chantal Csajka

  6. Critical Care Department, Joan XXIII University Hospital, Institut d’Investigació Sanitària Pere Virgili (IISPV), Universitat Rovira I Virgili, Tarragona, Spain

    Alejandro Rodríguez

  7. Centro de Investigación Biomédica En Red de Enfermedades Respiratorias (CIBERES), Madrid, Spain

    Alejandro Rodríguez, Joan Ramon Badia, Ignacio Martín-Loeches & Dolors Soy

  8. Respiratory Intensive Care Unit, Hospital Clínic de Barcelona, Barcelona, Spain

    Joan Ramon Badia

  9. Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS) – Fundació Clínic per la Recerca Biomèdica, Barcelona, Spain

    Joan Ramon Badia & Dolors Soy

  10. Multidisciplinary Intensive Care Research Organization (MICRO), Critical Care Department, St James University Hospital, Trinity Centre for Health Sciences, Dublin, Ireland

    Ignacio Martín-Loeches

Authors
  1. Marta Ulldemolins
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  6. Joan Ramon Badia
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  7. Ignacio Martín-Loeches
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  8. Dolors Soy
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Contributions

MU, IML, and DS designed the study and wrote the study protocol. MU, MLS, JRB, and AR performed sample and data collection. MU, CB, CC, and DS developed data analysis. MU, CB, IML, and DS drafted the manuscript. All authors critically reviewed the manuscript, and approved the final version.

Corresponding author

Correspondence to Marta Ulldemolins.

Ethics declarations

Preliminary results of this research were presented in the “XIII Jornadas en Modelización y Simulación en Biomedicina 2020” (25-26th November 2020) as an oral communication.

Ethics approval and consent to participate

The study was conducted following the Declaration of Helsinki guidelines. Authorization for the study was granted by the Spanish Regulatory Medicines Agency (code IEM-ANT-2012-1) and ethical approval was obtained from the local ethics committees. Written informed consent was obtained from each patient’s legally authorized representative.

Conflict of interest

The authors declare no competing interests.

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Supplementary information

Figure 1S

Scatterplot of the relationship between total ceftriaxone concentration (mg/L) and unbound fraction (ƒu). (PNG 274 kb)

Figure 2S

Scatterplot of the relationship between albumin plasma concentrations (g/L) and unbound ceftriaxone fraction (ƒu). (PNG 272 kb)

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Ulldemolins, M., Bastida, C., Llauradó-Serra, M. et al. Once-daily 1 g ceftriaxone optimizes exposure in patients with septic shock and hypoalbuminemia receiving continuous veno-venous hemodiafiltration. Eur J Clin Pharmacol 77, 1169–1180 (2021). https://doi.org/10.1007/s00228-021-03100-5

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