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Risk factors for target non-attainment during empirical treatment with β-lactam antibiotics in critically ill patients

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An Erratum to this article was published on 28 March 2015

Abstract

Purpose

Risk factors for β-lactam antibiotic underdosing in critically ill patients have not been described in large-scale studies. The objective of this study was to describe pharmacokinetic/pharmacodynamic (PK/PD) target non-attainment envisioning empirical dosing in critically ill patients and considering a worst-case scenario as well as to identify patient characteristics that are associated with target non-attainment.

Methods

This analysis uses data from the DALI study, a prospective, multi-centre pharmacokinetic point-prevalence study. For this analysis, we assumed that these were the concentrations that would be reached during empirical dosing, and calculated target attainment using a hypothetical target minimum inhibitory concentration (MIC), namely the susceptibility breakpoint of the least susceptible organism for which that antibiotic is commonly used. PK/PD targets were free drug concentration maintained above the MIC of the suspected pathogen for at least 50 % and 100 % of the dosing interval respectively (50 % and 100 % f T >MIC). Multivariable analysis was performed to identify factors associated with inadequate antibiotic exposure.

Results

A total of 343 critically ill patients receiving eight different β-lactam antibiotics were included. The median (interquartile range) age was 60 (47–73) years, APACHE II score was 18 (13–24). In the hypothetical situation of empirical dosing, antibiotic concentrations remained below the MIC during 50 % and 100 % of the dosing interval in 66 (19.2 %) and 142 (41.4 %) patients respectively. The use of intermittent infusion was significantly associated with increased risk of non-attainment for both targets; creatinine clearance was independently associated with not reaching the 100 % f T >MIC target.

Conclusions

This study found that—in empirical dosing and considering a worst-case scenario—19 % and 41 % of the patients would not achieve antibiotic concentrations above the MIC during 50 % and 100 % of the dosing interval. The use of intermittent infusion (compared to extended and continuous infusion) was the main determinant of non-attainment for both targets; increasing creatinine clearance was also associated with not attaining concentrations above the MIC for the whole dosing interval. In the light of this study from 68 ICUs across ten countries, we believe current empiric dosing recommendations for ICU patients are inadequate to effectively cover a broad range of susceptible organisms and need to be reconsidered.

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Acknowledgments

This project has received funding from the European Society of Intensive Care Medicine’s European Critical Care Research Network (ESICM ECCRN), and the Royal Brisbane and Women’s Hospital Foundation. Jason Roberts is funded in part by a National Health and Medical Research Council of Australia Research Fellowship (NHMRC APP1048652).

Conflicts of interest

The authors declare that they have no conflict of interest.

Author information

Authors and Affiliations

  1. Department of Critical Care Medicine, Ghent University Hospital, De Pintelaan 185, 9000, Ghent, Belgium

    Jan J. De Waele

  2. Burns Trauma and Critical Care Research Centre, The University of Queensland, Brisbane, Australia

    J. Lipman, D. Koulenti, A. A. Udy, T. Starr, S. C. Wallis & J. A. Roberts

  3. Royal Brisbane and Women’s Hospital, Brisbane, Australia

    J. Lipman & J. A. Roberts

  4. Hacettepe University Hospital, Ankara, Turkey

    M. Akova

  5. Azienda Ospedaliera Universitaria Santa Maria della Misericordia, Udine, Italy

    M. Bassetti

  6. Attikon University Hospital, University of Athens Medical School, Athens, Greece

    G. Dimopoulos

  7. Helsinki University Hospital, Helsinki, Finland

    M. Kaukonen

  8. Department of Epidemiology and Preventive Medicine, Monash University, Australian and New Zealand Intensive Care Research Centre (ANZIC RC), Melbourne, Australia

    M. Kaukonen

  9. Hospital Nord, Marseille, France

    C. Martin

  10. Centre Hospitalier Universitaire Bichat-Claude Bernard, Paris, France

    P. Montravers

  11. CIBERES, Vall d’Hebron Institut of Research, Barcelona, Spain

    J. Rello

  12. St George’s Healthcare NHS Trust and St George’s University of London, London, UK

    A. Rhodes

  13. Department of Intensive Care and Hyperbaric Medicine, The Alfred Hospital, Melbourne, VIC, Australia

    A. A. Udy

Authors
  1. Jan J. De Waele
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  2. J. Lipman
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  3. M. Akova
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  4. M. Bassetti
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  5. G. Dimopoulos
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  6. M. Kaukonen
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  7. D. Koulenti
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  8. C. Martin
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  9. P. Montravers
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  10. J. Rello
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Corresponding author

Correspondence to Jan J. De Waele.

Additional information

On behalf of the DALI study authors (Appendix).

Appendix: Participating investigators

Appendix: Participating investigators

Author name

Affiliation

Jason A. Roberts

Burns Trauma and Critical Care Research Centre, The University of Queensland, Brisbane, Australia

Royal Brisbane and Women’s Hospital, Brisbane, Australia

Jeffrey Lipman

Burns Trauma and Critical Care Research Centre, The University of Queensland, Brisbane, Australia

Royal Brisbane and Women’s Hospital, Brisbane, Australia

Therese Starr

Royal Brisbane and Women’s Hospital, Brisbane, Australia

Steven C. Wallis

Burns Trauma and Critical Care Research Centre, The University of Queensland, Brisbane, Australia

Sanjoy Paul

Queensland Clinical Trials & Biostatistics Centre, School of Population Health, The University of Queensland, Brisbane, Australia

Antonio Margarit Ribas

Hospital Nostra Senyora de Meritxell, Escaldes-Engordany, Andorra

Jan J. De Waele

Ghent University Hospital, Ghent, Belgium

Luc De Crop

Ghent University Hospital, Ghent, Belgium

Herbert Spapen

Universitair Ziekenhuis Brussels, Brussels, Belgium

Joost Wauters

Universitair Ziekenhuis Gasthuisberg, Leuven, Brussels

Thierry Dugernier

Clinique Saint Pierre, Ottignies, Belgium

Philippe Jorens

Universitair Ziekenhuis Antwerpen, Edegem, Belgium

Ilse Dapper

Algemeen Ziekenhuis Monica, Deurne, Belgium

Daniel De Backer

Erasme University Hospital, Brussels, Belgium

Fabio S. Taccone

Erasme University Hospital, Brussels, Belgium

Jordi Rello

Vall d’Hebron Institut of Research, Universitat Autonoma de Barcelona, Spain

Centro de Investigación Biomedica En Red- Enfermedades Respiratorias (CibeRes)

Laura Ruano

Vall d’Hebron Institut of Research, Universitat Autonoma de Barcelona, Spain

Centro de Investigación Biomedica En Red- Enfermedades Respiratorias (CibeRes)

Elsa Afonso

Hospital Universitari Vall d’Hebron, Vall d’Hebron Institut of Research, Universitat Autonoma de Barcelona, Spain

Centro de Investigación Biomedica En Red- Enfermedades Respiratorias (CibeRes)

Francisco Alvarez-Lerma

Hospital Del Mar, Parc Salut Mar, Barcelona, Spain

Maria Pilar Gracia-Arnillas

Hospital Del Mar, Parc Salut Mar, Barcelona, Spain

Francisco Fernández

Centro Médico Delfos, Barcelona

Neus Feijoo

Hospital General de L’Hospitalet, Barcelona, Spain

Neus Bardolet

Hospital General de L’Hospitalet, Barcelona, Spain

Assumpta Rovira

Hospital General de L’Hospitalet, Barcelona, Spain

Pau Garro

Hospital General de Granollers, Barcelona, Spain

Diana Colon

Hospital General de Granollers, Barcelona, Spain

Carlos Castillo

Hospital Txagorritxu, Vitoria, Spain

Juan Fernado

Hospital Txagorritxu, Vitoria, Spain

Maria Jesus Lopez

Hospital Universitario de Burgos, Burgos, Spain

Jose Luis Fernandez

Hospital Universitario de Burgos, Burgos, Spain

Ana Maria Arribas

Hospital Universitario de Burgos, Burgos, Spain

Jose Luis Teja

Hospital Universitario Marques de Valdecilla, Santander, Spain

Elsa Ots

Hospital Universitario Marques de Valdecilla, Santander, Spain

Juan Carlos Montejo

Hospital Universitario 12 de Octubre, Madrid, Spain

Mercedes Catalan

Hospital Universitario 12 de Octubre, Madrid, Spain

Isidro Prieto

Hospital Ramon y Cajal, Madrid, Spain

Gloria Gonzalo

Hospital Ramon y Cajal, Madrid, Spain

Beatriz Galvan

Hospital Universitario La Paz, Madrid, Spain

Miguel Angel Blasco

Hospital Universitario Severo Ochoa, Madrid, Spain

Estibaliz Meyer

Hospital Universitario Severo Ochoa, Madrid, Spain

Frutos Del Nogal

Hospital Universitario Severo Ochoa, Madrid, Spain

Loreto Vidaur

Hospital Universitario de Donostia, Donostia, Spain

Rosa Sebastian

Hospital Universitario de Donostia, Donostia, Spain

Pila Marco Garde

Hospital Universitario de Donostia, Donostia, Spain

Maria del Mar Martin Velasco

Hospital Universitario Nuestra Señora de Candelaria, Spain

Rafael Zaragoza Crespo

Hospital Universitario Dr. Peset, Spain

Mariano Esperatti

Institut Clínic del Tòrax, Hospital Clinic, IDIBAPS, Barcelona, Spain

Centro de Investigación Biomedica En; Red- Enfermedades Respiratorias (CibeRes)

Antoni Torres

Institut Clínic del Tòrax, Hospital Clinic, IDIBAPS, Barcelona, Spain

Centro de Investigación Biomedica En Red- Enfermedades Respiratorias (CibeRes)

Philippe Montravers

Centre Hospitalier Universitaire Bichat-Claude Bernard, AP-HP, Université Paris VII, Paris, France

Olivier Baldesi

Centre Hospitalier Pays D Aix, Aix en Provence, France and AzuRea Group

Herve Dupont

Centre Hospitalier Universitaire d’Amiens, Amiens, France

Yazine Mahjoub

Centre Hospitalier-Universitaire d’Amiens, Amiens, France and AzuRea Group

Sigismond Lasocki

Centre Hospitalier-Universitaire d’Angers, Angers, France

Jean Michel Constantin

Centre Hospitalier Universitaire de Clermont-Ferrand, Clermont-Ferrand, France and AzuRea Group

Jean François Payen

Centre Hospitalier-Universitaire Grenoble, Grenoble France and AzuRea Group

Claude Martin

Hopital Nord, Marseille, France; AzuRea Group, France

Jacques Albanese

Hopital Nord, Marseille, France and AzuRea Group

Yannick Malledant

Hôpital Pontchaillou, Rennes, France

Julien Pottecher

University Hospital, Strasbourg, France and AzuRea Group

Jean-Yves Lefrant

Centre Hospitalier-Universitaire Nimes, Nimes France and AzuRea Group

Samir Jaber

Hospitalier-Universitaire Montpellier, Montpellier, France and AzuRea Group

Olivier Joannes-Boyau

Centre Hospitalier-Universitaire Bordeaux, Bordeaux, France and AzuRea Group

Christophe Orban

Centre Hospitalier-Universitaire Nice, Nice, France and AzuRea Group

Marlies Ostermann

St Thomas’ Hospital, London, UK

Catherine McKenzie

St Thomas’ Hospital, London, UK

Willaim Berry

St Thomas’ Hospital, London, UK

John Smith

St Thomas’ Hospital, London, UK

Katie Lei

St Thomas’ Hospital, London, UK

Francesca Rubulotta

Charing Cross Hospital, Imperial Healthcare NHS Trust, London, UK

Anthony Gordon

Charing Cross Hospital, Imperial Healthcare NHS Trust, London, UK

Stephen Brett

Hammersmith Hospital, Imperial Healthcare NHS Trust, London, UK

Martin Stotz

St Mary’s Hospital, Imperial Healthcare NHS Trust, London, UK

Maie Templeton

St Mary’s Hospital, Imperial Healthcare NHS Trust, London, UK

Andrew Rhodes

St George’s Hospital, St George’s Healthcare NHS Trust, London, UK

Claudia Ebm

St George’s Hospital, St George’s Healthcare NHS Trust, London, UK

Carl Moran

St George’s Hospital, St George’s Healthcare NHS Trust, London, UK

Kirsi-Maija Kaukonen

Helsinki University Central Hospital, Helsinki, Finland

Ville Pettilä

Helsinki University Central Hospital, Helsinki, Finland

George Dimopoulos

Attikon University Hospital, Athens, Greece

Despoina Koulenti

Attikon University Hospital, Athens, Greece

Aglaia Xristodoulou

Attikon University Hospital, Athens, Greece

Vassiliki Theodorou

University Hospital of Alexandroupolis, Alexandroupolis, Greece

Georgios Kouliatsis

University Hospital of Alexandroupolis, Alexandroupolis, Greece

Stylianos Fotakis

University Hospital of Alexandroupolis, Alexandroupolis, Greece

Georgios Anthopoulos

251 Air Force General Hospital of Athens, Athens, Greece

George Choutas

251 Air Force General Hospital of Athens, Athens, Greece

Thanos Rantis

251 Air Force General Hospital of Athens, Athens, Greece

Stylianos Karatzas

General Hospital of Athens ‘Hippokrateion’, Athens, Greece

Margarita Balla

General Hospital of Athens ‘Hippokrateion’, Athens, Greece

Metaxia Papanikolaou

General Hospital of Athens ‘Hippokrateion’, Athens, Greece

Pavlos Myrianthefs

‘Aghioi Anargyroi’ Hospita, Athens, Greece

Alexandra Gavala

‘Aghioi Anargyroi’ Hospita, Athens, Greece

Georgios Fildisis

‘Aghioi Anargyroi’ Hospita, Athens, Greece

Antonia Koutsoukou

Sotiria General Hospital, Athens, Greece

Magdalini Kyriakopoulou

Sotiria General Hospital, Athens, Greece

Kalomoira Petrochilou

Sotiria General Hospital, Athens, Greece

Maria Kompoti

‘Thriassio’ General Hospital of Eleusi, Athen, Greece

Martha Michalia

‘Thriassio’ General Hospital of Eleusi, Athen, Greece

Fillis-Maria Clouva-Molyvdas

‘Thriassio’ General Hospital of Eleusi, Athen, Greece

Georgios Gkiokas

Aretaieion University Hospital, Athens, Greece

Fotios Nikolakopoulos

Aretaieion University Hospital, Athens, Greece

Vasiliki Psychogiou

Aretaieion University Hospital, Athens, Greece

Polychronis Malliotakis

University Hospital Herakleion, Crete, Greece

Evangelia Akoumianaki

University Hospital Herakleion, Crete, Greece

Emmanouil Lilitsis

University Hospital Herakleion, Crete, Greece

Vassilios Koulouras

University Hospital of Ioannina, Ioannina, Greece

George Nakos

University Hospital of Ioannina, Ioannina, Greece

Mihalis Kalogirou

University Hospital of Ioannina, Ioannina, Greece

Apostolos Komnos

General Hospital of Larisa, Larisa, Greece

Tilemachos Zafeiridis

General Hospital of Larisa, Larisa, Greece

Achilleas Chovas

General Hospital of Larisa, Larisa, Greece

Kostoula Arvaniti

General Hospital of Thessaloniki ‘G. Papageorgiou’, Thessaloniki, Greece

Dimitrios Matamis

General Hospital of Thessaloniki ‘G. Papageorgiou’, Thessaloniki, Greece

Christos Chaintoutis

General Hospital of Thessaloniki ‘G. Papageorgiou’, Thessaloniki, Greece

Christina Kydona

General Hospital of Thessaloniki ‘Hippokrateion’, Thessaloniki, Greece

Nikoleta Gritsi-Gerogianni

General Hospital of Thessaloniki ‘Hippokrateion’, Thessaloniki, Greece

Tatiana Giasnetsova

General Hospital of Thessaloniki ‘Hippokrateion’, Thessaloniki, Greece

Maria Giannakou

Ahepa University Hospital, Thessaloniki, Greece

Ioanna Soultati

Ahepa University Hospital, Thessaloniki, Greece

Ilias Chytas

Ahepa University Hospital, Thessaloniki, Greece

Eleni Antoniadou

General Hospital ‘G. Gennimatas’, Thessaloniki, Greece

Elli Antipa

General Hospital ‘G. Gennimatas’, Thessaloniki, Greece

Dimitrios Lathyris

General Hospital ‘G. Gennimatas’, Thessaloniki, Greece

Triantafyllia Koukoubani

General Hospital of Trikala, Trikala, Greece

Theoniki Paraforou

General Hospital of Trikala, Trikala, Greece

Kyriaki Spiropoulou

General Hospital of Trikala, Trikala, Greece

Vasileios Bekos

Naval Hospital of Athens, Athens, Greece

Anna Spring

Naval Hospital of Athens, Athens, Greece

Theodora Kalatzi

Naval Hospital of Athens, Athens, Greece

Hara Nikolaou

‘Aghia Olga-Konstantopouleion’ General Hospital, Athens, Greece

Maria Laskou

‘Aghia Olga-Konstantopouleion’ General Hospital, Athens, Greece

Ioannis Strouvalis

‘Aghia Olga-Konstantopouleion’ General Hospital, Athens, Greece

Stavros Aloizos

General Hospital of Athens ‘NIMITS’, Athens, Greece

Spyridon Kapogiannis

General Hospital of Athens ‘NIMITS’, Athens, Greece

Ourania Soldatou

General Hospital of Athens ‘NIMITS’, Athens, Greece

Matteo Bassetti

Azienda Ospedaliera Universitaria Santa Maria della Misericordia, Udine, Italy

Chiara Adembri

Azienda Ospedaliero Universitaria Careggi, Florence, Italy

Gianluca Villa

Azienda Ospedaliero Universitaria Careggi, Florence, Italy

Antonio Giarratano

Università degli Studi di Palermo, Palermo, Italy

Santi Maurizio Raineri

Università degli Studi di Palermo, Palermo, Italy

Andrea Cortegiani

Università degli Studi di Palermo, Palermo, Italy

Francesca Montalto

Università degli Studi di Palermo, Palermo, Italy

Maria Teresa Strano

Università degli Studi di Palermo, Palermo, Italy

V. Marco Ranieri

San Giovanni-Battista Molinette, Turin, Italy

Claudio Sandroni

Catholic University School of Medicine, Rome, Italy

Gennaro De Pascale

Catholic University School of Medicine, Rome, Italy

Alexandre Molin

University of Genoa, Genoa, Italy

Paolo Pelosi

University of Genoa, Genoa, Italy

Luca Montagnani

Universitaria San Martino, Genova, Italy

Rosario Urbino

Universitaria S.Giovanni Battista della Città di Torino, Turin, Italy

Ilaria Mastromauro

Universitaria S.Giovanni Battista della Città di Torino, Turin, Italy

Francesco G. De Rosa

Universitaria S.Giovanni Battista della Città di Torino, Turin, Italy

V. Marco Ranieri

Universitaria S.Giovanni Battista della Città di Torino, Turin, Italy

Teresa Cardoso

Hospital de Santo António, Porto, Portugal

Susana Afonso

Hospital de St António dos Capuchos, Lisbon, Portgual

João Gonçalves-Pereira

Hospital de São Francisco Xavier, Lisbon, Portugal

João Pedro Baptista

Hospital de Universidade de Coimbra, Coimbra, Portugal

Murat Akova

Hacettepe University School of Medicine, Ankara, Turkey

Arife Özveren

Hacettepe University School of Medicine, Ankara, Turkey

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De Waele, J.J., Lipman, J., Akova, M. et al. Risk factors for target non-attainment during empirical treatment with β-lactam antibiotics in critically ill patients. Intensive Care Med 40, 1340–1351 (2014). https://doi.org/10.1007/s00134-014-3403-8

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