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Exposure levels and target attainment of piperacillin/tazobactam in adult patients admitted to the intensive care unit: a prospective observational study

Taux d’exposition et atteinte des cibles de pipéracilline/tazobactam chez la patientèle adulte admise aux soins intensifs : une étude observationnelle prospective

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Abstract

Purpose

The objective of this study was to evaluate the exposure and the pharmacodynamic target attainment of piperacillin/tazobactam (PTZ) in adult critically ill patients.

Methods

We conducted a prospective observational study in the intensive care unit (ICU) of the Hôpital du Sacré-Cœur de Montréal (a Level I trauma centre in Montreal, QC, Canada) between January 2021 and June 2022. We included patients aged 18 yr or older admitted to the ICU who received PTZ by intravenous administration. Demographic and clinical characteristics were collected, and clinical scores were calculated. On study day 1 of antimicrobial therapy, three blood samples were collected at the following timepoints: one hour after PTZ dose administration and at the middle and at the end of the dosing interval. The sampling schedule was repeated on days 4 and 7 of therapy if possible. Samples were analyzed by ultra-high performance liquid chromatography with diode array detector to determine the total piperacillin concentration. Middle- and end-of-interval concentrations were used for target attainment analyses, and were defined as a concentration above the minimal inhibitory concentration of 16 mg·L−1, corresponding to the breakpoint of Enterobacteriaceae and Pseudomonas aeruginosa.

Results

Forty-three patients were recruited and 202 blood samples were analyzed. The most prevalent dose was 3/0.375 g every six hours (n = 50/73 doses administered, 68%) with a 30-min infusion. We observed marked variability over the three sampling timepoints, and the median [interquartile range] piperacillin concentrations at peak, middle of interval, and end of interval were 109.4 [74.0–152.3], 59.3 [21.1–74.4], and 25.3 [6.8–44.6] mg·L−1, respectively. When assessing target attainment, 37% of patients did not reach the efficacy target of a trough concentration of 16 mg·L−1. The majority of patients who were underexposed were patients with normal to augmented renal clearance.

Conclusion

In this prospective observational study of adult ICU patients receiving intravenous PTZ, a large proportion had subtherapeutic concentrations of piperacillin. This was most notable in patients with normal to augmented renal clearance. More aggressive dosage regimens may be required for this subpopulation to ensure attainment of efficacy targets.

Résumé

Objectif

L’objectif de cette étude était d’évaluer l’exposition et l'atteinte des cibles pharmacodynamiques de la pipéracilline/tazobactam (PTZ) chez la patientèle adulte aux soins intensifs.

Méthodes

Nous avons réalisé une étude observationnelle prospective dans l'unité de soins intensifs (USI) de l'Hôpital du Sacré-Cœur de Montréal (un centre de traumatologie de niveau 1 à Montréal, QC, Canada) entre janvier 2021 et juin 2022. Nous avons inclus les patient·es adultes âgé·es de 18 ans ou plus admis·es à l'USI ayant reçu de la PTZ par administration intraveineuse. Les caractéristiques démographiques et cliniques ont été recueillies, et les scores cliniques ont été calculés. Au jour 1 de la thérapie antimicrobienne, trois échantillons sanguins ont été prélevés aux moments suivants : 1 h après l'administration de la dose de PTZ, au milieu et à la fin de l'intervalle d'administration. Le calendrier d’échantillonnage a été répété aux jours 4 et 7 de la thérapie si possible. Les échantillons ont été analysés par chromatographie liquide à ultra-haute performance avec détecteur à diodes pour déterminer la concentration totale de pipéracilline. Les concentrations du milieu et de fin d'intervalle ont été utilisées pour les analyses d'atteinte de cible, définie comme une concentration supérieure à la concentration minimale inhibitrice de 16 mg·L-1, associée aux Enterobacteriaceae et au Pseudomonas aeruginosa.

Résultats

Quarante-trois patient·es ont été recruté·es et 202 échantillons sanguins ont été analysés. La dose la plus prévalente était une dose de 3/0,375 g aux 6 h (n = 50/73 doses administrées, 68 %) avec une perfusion sur 30 min. Nous avons observé une variabilité marquée aux trois temps de prélèvement, et les concentrations médianes [intervalle interquartile] de pipéracilline au pic, au milieu et à la fin de l'intervalle étaient respectivement de 109,4 [74,0-152,3], 59,3 [21,1-74,4] et 25,3 [6,8-44,6] mg·L−1. Lors de l'évaluation de l'atteinte de la cible, 37 % des patient·es n'ont pas atteint la cible d'efficacité d'une concentration de 16 mg·L−1 à la fin de l’intervalle posologique. La majorité des patient·es sous-exposé·es étaient des personnes dont la clairance rénale était normale ou augmentée.

Conclusion

Dans cette étude observationnelle prospective de patient·es adultes aux soins intensifs recevant de la PTZ par voie intraveineuse, une grande proportion de patient·es présentait des concentrations sous-thérapeutiques de pipéracilline. Ceci était plus marqué chez les patient·es ayant une clairance rénale normale ou augmentée. Des schémas posologiques plus agressifs pourraient être nécessaires pour cette sous-population afin de favoriser l’atteinte des cibles d’efficacité.

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Authors and Affiliations

  1. Faculty of Pharmacy, Université de Montréal, Montreal, QC, Canada

    Amélie Marsot PhD, Thomas Pesout BSc & David Williamson BPharm, PhD

  2. Laboratoire de Suivi Thérapeutique Pharmacologique et Pharmacocinétique, Faculty of Pharmacy, Université de Montréal, Montreal, QC, Canada

    Ibrahim El-Haffaf MSc & Amélie Marsot PhD

  3. Centre de recherche, CHU Sainte-Justine, Montréal, QC, Canada

    Amélie Marsot PhD

  4. CIUSSS-NIM-Hôpital du Sacré-Cœur de Montréal and CIUSSS-NIM Research Center, Montreal, QC, Canada

    Djamila Hachemi PharmD, Thomas Pesout BSc, Virginie Williams PhD, Marc-André Smith MD, Martin Albert MD, FRCPC, FACP & David Williamson BPharm, PhD

  5. Faculty of Medicine, Université de Montréal, Montreal, QC, Canada

    Martin Albert MD, FRCPC, FACP

  6. Faculty of Pharmacy, Université de Montréal, 2940 chemin de Polytechnique, Montreal, QC, H3T 1J4, Canada

    Ibrahim El-Haffaf MSc

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Correspondence to Ibrahim El-Haffaf MSc.

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Author contributions

Amélie Marsot, David Williamson, Martin Albert, Marc-André Smith, and Ibrahim El-Haffaf contributed to study conception and design. David Williamson, Djamila Hachemi, Thomas Pesout, and Virginie Williams collected and provided the clinical data. Ibrahim El-Haffaf quantified blood samples and analyzed the data. Ibrahim El-Haffaf, Amélie Marsot, and David Williamson prepared the manuscript draft. Amélie Marsot and David Williamson supervised the work.

Disclosures

The authors declare no conflicts of interest.

Funding statement

This project has received funding from the Canadian Society of Hospital Pharmacists and from the Fonds Servier granted by the Faculty of Pharmacy of Université de Montréal. Amélie Marsot acknowledges support from the Fonds de Recherche du Québec-Santé (FRQS) Research Scholars—Junior 1 (Young Researcher Establishment) Career Scholarship. David Williamson acknowledges support from the FRQS Clinical Research Scholars – Junior 2. Ibrahim El-Haffaf acknowledges receiving a scholarship from the Faculty of Pharmacy of Université de Montréal and from the FRQS (Doctoral Training Scholarship). The funders had no role in the design and conduct of the study, the collection, management, analysis, and interpretation of the data, the preparation, review, or approval of the manuscript, or the decision to submit the manuscript for publication.

Prior conference presentations

Data reported in this manuscript were presented in part in the 33rd European Congress of Clinical Microbiology & Infectious Diseases (15–18 April 2023, Copenhagen, Denmark) and in the 90th edition of the Congrès de l’Acfas (8–12 May 2023, Montreal, QC, Canada).

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This submission was handled by Dr. Alexis F. Turgeon, Associate Editor, Canadian Journal of Anesthesia/Journal canadien d’anesthésie.

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El-Haffaf, I., Marsot, A., Hachemi, D. et al. Exposure levels and target attainment of piperacillin/tazobactam in adult patients admitted to the intensive care unit: a prospective observational study. Can J Anesth/J Can Anesth 71, 511–522 (2024). https://doi.org/10.1007/s12630-023-02689-8

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