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Antifungal de-escalation was not associated with adverse outcome in critically ill patients treated for invasive candidiasis: post hoc analyses of the AmarCAND2 study data

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Abstract

Purpose

Systemic antifungal therapy (SAT) of invasive candidiasis needs to be initiated immediately upon clinical suspicion. Controversies exist about adequate time and potential harm of antifungal de-escalation (DE) in documented and suspected candidiasis in ICU patients. Our objective was to investigate whether de-escalation within 5 days of antifungal initiation is associated with an increase of the 28-day mortality in SAT-treated non-neutropenic adult ICU patients.

Methods

From the 835 non-neutropenic adults recruited in the multicenter prospective observational AmarCAND2 study, we selected the patients receiving systemic antifungal therapy for a documented or suspected invasive candidiasis in the ICU and who were still alive 5 days after SAT initiation. They were included into two groups according to the occurrence of observed SAT de-escalation before day 6. The average causal SAT de-escalation effect on 28-day mortality was evaluated by using a double robust estimation.

Results

Among the 647 included patients, early de-escalation at day 5 after antifungal initiation occurred in 142 patients (22 %), including 48 (34 %) patients whose SAT was stopped before day 6. After adjustment for the baseline confounders, early SAT de-escalation was the solely factor not associated with increased 28-day mortality (RR 1.12, 95 % CI 0.76–1.66).

Conclusion

In non-neutropenic critically ill adult patients with documented or suspected invasive candidiasis, SAT de-escalation within 5 days was not related to increased day-28 mortality but it was associated with decreased SAT consumption. These results suggest for the first time that SAT de-escalation may be safe in these patients.

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Acknowledgments

Members of the independent scientific committee: Olivier Leroy (MD, medical intensivist), Jean-François Timsit (MD, PhD, medical intensivist, epidemiologist), Jean-Pierre Gangneux (MD, PhD, mycologist), Elie Azoulay (MD, PhD, medical intensivist), Jean-Michel Constantin (MD, PhD, anesthesiologist and intensivist), Hervé Dupont (MD, PhD, anesthesiologist and intensivist), Olivier Lortholary (MD, PhD, infectious diseases specialist), Jean-Paul Mira (MD, PhD, medical intensivist), Philippe Montravers (MD, PhD, anesthesiologist and intensivist), Pierre-François Perrigault (MD, anesthesiologist and intensivist). Manuscript preparation: the authors thank Celine Feger (MD; EMIBiotech), who provided assistance in preparing and editing the manuscript and Romain Pirrachio (MD, PhD; University of California, San Francisco) who reviewed statistical analysis.

Author information

Authors and Affiliations

  1. Inserm UMR 1137-IAME Team 5-DeSCID: Decision SCiences in Infectious Diseases, Control and Care INSERM/Paris Diderot, Sorbonne Paris Cité University, Paris, France

    Sébastien Bailly & Jean-François Timsit

  2. Grenoble 1 University, U823, Rond-point de la Chantourne, 38700, La Tronche, France

    Sébastien Bailly

  3. Medical ICU, Chatiliez Hospital, Tourcoing, France

    Olivier Leroy

  4. Paris Diderot Sorbonne Cite University, and Anaesthesiology and Critical Care Medicine, Bichat-Claude Bernard University Hospital, APHP, Paris, France

    Philippe Montravers

  5. Perioperative Medicine Department, Clermont-Ferrand University Hospital, Clermont-Ferrand, France

    Jean-Michel Constantin

  6. Surgical ICU, Amiens University Hospital, Amiens, France

    Hervé Dupont

  7. Inserm UMR 1181 “Biostatistics, Biomathematics, Pharmacoepidemiology and Infectious Diseases” (B2PHI), 75015, Paris, France

    Didier Guillemot

  8. University Paris Descartes, Necker Pasteur Center for Infectious Diseases, Necker Enfants-Malades Hospital, IHU Imagine, Paris, France

    Olivier Lortholary

  9. Pasteur Institute, National Reference Center for Invasive Mycoses and Antifungals, CNRS URA3012, Paris, France

    Olivier Lortholary

  10. Medical ICU, Cochin University Hospital, APHP, Paris, France

    Jean-Paul Mira

  11. Paris Descartes, Sorbonne Paris Cité University, Paris, France

    Jean-Paul Mira

  12. Medical-Surgical ICU, Montpellier University Hospital, Montpellier, France

    Pierre-François Perrigault

  13. Mycology, Rennes University Hospital, Rennes, France

    Jean-Pierre Gangneux

  14. Medical ICU, Saint-Louis University Hospital, Paris, France

    Elie Azoulay

  15. Medical and Infectious Diseases ICU, Paris Diderot University/Bichat University Hospital, APHP, 46 rue Henri Huchard, Paris, 75018, France

    Jean-François Timsit

Authors
  1. Sébastien Bailly
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  2. Olivier Leroy
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  3. Philippe Montravers
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  4. Jean-Michel Constantin
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  5. Hervé Dupont
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  6. Didier Guillemot
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  7. Olivier Lortholary
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  8. Jean-Paul Mira
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  9. Pierre-François Perrigault
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  10. Jean-Pierre Gangneux
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  11. Elie Azoulay
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  12. Jean-François Timsit
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Corresponding author

Correspondence to Sébastien Bailly.

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Funding

This work was supported by MSD France, which was the sponsor.

Conflicts of interest

Authors had full access to the database, and the statistical analyses were conducted by an academic team: Biostatistics Unit, Lille University Hospital, Lille, France, which worked in full independence from MSD.

EA has been a consultant to Astellas, Alexion, Cubist, Gilead, and MSD, and has benefited from grants to his research unit from Gilead and Pfizer. J-MC has been a consultant to MSD. HD has been a consultant to Astellas, Gilead, Cubist, Astrazeneca, Merck, and Pfizer. J-PG has been a consultant to Astellas, Gilead, Merck, and Pfizer. DG has benefited from grants of the Principality of Monaco to his research unit. O Leroy has been consultant to Astellas, Gilead, Merck, Novartis, Pfizer, and Sanofi. O Lortholary has been consultant to Gilead Sciences and Novartis and member of the speaker’s bureau of Astellas, Basilea, Merck, Pfizer, and Sanofi. J-PM has been a consultant to Astellas, Gilead, MSD, and LFB. PM has been a consultant to Astra-Zeneca, Cubist, MSD, Pfizer, and TMC. P-FP has been a consultant to MSD and Pfizer. JFT has given lectures for symposiums set up by Astellas, Pfizer, MSD, 3M, Novartis, and Gilead; has benefited from unrestricted research grants to his research unit from 3M, MSD, and Astellas; and has been a consultant involved in scientific boards for MSD, 3M, and Bayer. SB has no conflict of interest.

Additional information

Take-home message: Early de-escalation of systemic antifungal treatments is not consensual. A causal analysis based on a multicenter prospective cohort in 87 French ICUs has shown that antifungal de-escalation within a 5-day interval is safe in SAT-treated non-neutropenic adult intensive care unit patients.

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Bailly, S., Leroy, O., Montravers, P. et al. Antifungal de-escalation was not associated with adverse outcome in critically ill patients treated for invasive candidiasis: post hoc analyses of the AmarCAND2 study data. Intensive Care Med 41, 1931–1940 (2015). https://doi.org/10.1007/s00134-015-4053-1

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