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Open Access 16-06-2022 | Septicemia | Original

(1 → 3)-β-d-Glucan-guided antifungal therapy in adults with sepsis: the CandiSep randomized clinical trial

Authors: Frank Bloos, Jürgen Held, Stefan Kluge, Philipp Simon, Klaus Kogelmann, Geraldine de Heer, Sven-Olaf Kuhn, Dominik Jarczak, Johann Motsch, Gunther Hempel, Norbert Weiler, Andreas Weyland, Matthias Drüner, Matthias Gründling, Patrick Meybohm, Daniel Richter, Ulrich Jaschinski, Onnen Moerer, Ulf Günther, Dirk Schädler, Raphael Weiss, Christian Putensen, Ixchel Castellanos, Oliver Kurzai, Peter Schlattmann, Oliver A. Cornely, Michael Bauer, Daniel Thomas-Rüddel, the SepNet Study Group

Published in: Intensive Care Medicine | Issue 7/2022

Abstract

Purpose

To investigate whether (1 → 3)-β-d-Glucan (BDG)-guidance shortens time to antifungal therapy and thereby reduces mortality of sepsis patients with high risk of invasive Candida infection (ICI).

Methods

Multicenter, randomized, controlled trial carried out between September 2016 and September 2019 in 18 intensive care units enrolling adult sepsis patients at high risk for ICI. Patients in the control group received targeted antifungal therapy driven by culture results. In addition to targeted therapy, patients in the BDG group received antifungals if at least one of two consecutive BDG samples taken during the first two study days was ≥ 80 pg/mL. Empirical antifungal therapy was discouraged in both groups. The primary endpoint was 28-day-mortality.

Results

339 patients were enrolled. ICI was diagnosed in 48 patients (14.2%) within the first 96 h after enrollment. In the BDG-group, 48.8% (84/172) patients received antifungals during the first 96 h after enrollment and 6% (10/167) patients in the control group. Death until day 28 occurred in 58 of 172 patients (33.7%) in the BDG group and 51 of 167 patients (30.5%) in the control group (relative risk 1.10; 95% confidence interval, 0.80–1.51; p = 0.53). Median time to antifungal therapy was 1.1 [interquartile range (IQR) 1.0–2.2] days in the BDG group and 4.4 (IQR 2.0–9.1, p < 0.01) days in the control group.

Conclusions

Serum BDG guided antifungal treatment did not improve 28-day mortality among sepsis patients with risk factors for but unexpected low rate of IC. This study cannot comment on the potential benefit of BDG-guidance in a more selected at-risk population.

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Singer M, Deutschman CS, Seymour CW et al (2016) The third international consensus definitions for sepsis and septic shock (Sepsis-3). JAMA 315:801–810PubMedPubMedCentral

Bassetti M, Giacobbe DR, Vena A et al (2019) Incidence and outcome of invasive candidiasis in intensive care units (ICUs) in Europe: results of the EUCANDICU project. Crit Care 23:219PubMedPubMedCentral

Koehler P, Stecher M, Cornely OA et al (2019) Morbidity and mortality of candidaemia in Europe: an epidemiologic meta-analysis. Clin Microbiol Infect 25:1200–1212PubMed

Kollef M, Micek S, Hampton N, Doherty JA, Kumar A (2012) Septic shock attributed to Candida infection: importance of empiric therapy and source control. Clin Infect Dis 54:1739–1746PubMed

Evans L, Rhodes A, Alhazzani W et al (2021) Surviving sepsis campaign: international guidelines for management of sepsis and septic shock 2021. Intensive Care Med. https://doi.org/10.1007/s00134-021CrossRefPubMedPubMedCentral

Pappas PG, Kauffman CA, Andes DR et al (2016) Clinical practice guideline for the management of candidiasis: 2016 update by the Infectious Diseases Society of America. Clin Infect Dis 62:e1-50PubMed

Martin-Loeches I, Antonelli M, Cuenca-Estrella M et al (2019) ESICM/ESCMID task force on practical management of invasive candidiasis in critically ill patients. Intensive Care Med 1:1

Ostrosky-Zeichner L, Alexander BD, Kett DH et al (2005) Multicenter clinical evaluation of the (1 → 3) beta-d-glucan assay as an aid to diagnosis of fungal infections in humans. Clin Infect Dis 41:654–659PubMed

Hanson KE, Pfeiffer CD, Lease ED et al (2012) β-d-glucan surveillance with preemptive anidulafungin for invasive candidiasis in intensive care unit patients: a randomized pilot study. PLoS ONE 7:e42282PubMedPubMedCentral

10.

Rouzé A, Loridant S, Poissy J et al (2017) Biomarker-based strategy for early discontinuation of empirical antifungal treatment in critically ill patients: a randomized controlled trial. Intensive Care Med 43:1668–1677PubMed

11.

De Pascale G, Posteraro B, D’Arrigo S et al (2020) (1,3)-β-d-Glucan-based empirical antifungal interruption in suspected invasive candidiasis: a randomized trial. Crit Care 24:550PubMedPubMedCentral

12.

Timsit JF, Azoulay E, Schwebel C et al (2016) Empirical micafungin treatment and survival without invasive fungal infection in adults with ICU-acquired sepsis, candida colonization, and multiple organ failure: the EMPIRICUS randomized clinical trial. JAMA 316:1555–1564PubMed

13.

O’Leary RA, Einav S, Leone M, Madách K, Martin C, Martin-Loeches I (2018) Management of invasive candidiasis and candidaemia in critically ill adults: expert opinion of the European Society of Anaesthesia Intensive Care Scientific Subcommittee. J Hosp Infect 98:382–390PubMed

14.

Bloos F, Held J, Schlattmann P et al (2018) (1,3)-β-d-glucan-based diagnosis of invasive Candida infection versus culture-based diagnosis in patients with sepsis and with an increased risk of invasive Candida infection (CandiSep): study protocol for a randomized controlled trial. Trials 19:472PubMedPubMedCentral

15.

Bloos F, Trips E, Nierhaus A et al (2016) Effect of sodium selenite administration and procalcitonin-guided therapy on mortality in patients with severe sepsis or septic shock: a randomized clinical trial. JAMA Intern Med 176:1266–1276PubMed

16.

Thomas-Rüddel D, Schlattmann P, Pletz M, Kurzai O, Bloos F (2021) Risk factors for invasive candida infection in critically ill patients—a systematic review and meta-analysis. Chest. https://doi.org/10.1016/j.chest.2021.08.081CrossRefPubMedPubMedCentral

17.

Cornely OA, Bassetti M, Calandra T et al (2012) ESCMID* guideline for the diagnosis and management of Candida diseases 2012: non-neutropenic adult patients. Clin Microbiol Infect 18(Suppl 7):19–37PubMed

18.

Pittet D, Monod M, Suter PM, Frenk E, Auckenthaler R (1994) Candida colonization and subsequent infections in critically ill surgical patients. Ann Surg 220:751–758PubMedPubMedCentral

19.

De Pauw B, Walsh TJ, Donnelly JP et al (2008) Revised definitions of invasive fungal disease from the European Organization for Research and Treatment of Cancer/Invasive Fungal Infections Cooperative Group and the National Institute of Allergy and Infectious Diseases Mycoses Study Group (EORTC/MSG) Consensus Group. Clin Infect Dis 46:1813–1821PubMed

20.

Brunkhorst FM, Engel C, Bloos F et al (2008) Intensive insulin therapy and pentastarch resuscitation in severe sepsis. N Engl J Med 358:125–139PubMed

21.

Brunkhorst FM, Oppert M, Marx G et al (2012) Effect of empirical treatment with moxifloxacin and meropenem vs meropenem on sepsis-related organ dysfunction in patients with severe sepsis: a randomized trial. JAMA 307:2390–2399PubMed

22.

Blumberg HM, Jarvis WR, Soucie JM et al (2001) Risk factors for candidal bloodstream infections in surgical intensive care unit patients: the NEMIS prospective multicenter study. The National Epidemiology of Mycosis Survey. Clin Infect Dis 33:177–186PubMed

23.

Piarroux R, Grenouillet F, Balvay P et al (2004) Assessment of preemptive treatment to prevent severe candidiasis in critically ill surgical patients. Crit Care Med 32:2443–2449PubMed

24.

Shan YS, Sy ED, Wang ST, Lee JC, Lin PW (2006) Early presumptive therapy with fluconazole for occult Candida infection after gastrointestinal surgery. World J Surg 30:119–126PubMed

25.

Ostrosky Zeichner L, Shoham S, Vazquez J et al (2014) MSG-01: a randomized, double-blind, placebo-controlled trial of caspofungin prophylaxis followed by preemptive therapy for invasive candidiasis in high-risk adults in the critical care setting. Clin Infect Dis 58:1219–1226PubMed

26.

Knitsch W, Vincent J-L, Utzolino S et al (2015) A randomized, placebo-controlled trial of preemptive antifungal therapy for the prevention of invasive candidiasis following gastrointestinal surgery for intra-abdominal infections. Clin Infect Dis 61:1671–1678PubMedPubMedCentral

27.

Schuster MG, Edwards JE, Sobel JD et al (2008) Empirical fluconazole versus placebo for intensive care unit patients: a randomized trial. Ann Intern Med 149:83–90PubMed

28.

Liss B, Cornely OA, Hoffmann D, Dimitriou V, Wisplinghoff H (2016) 1,3-β-d-Glucan contamination of common antimicrobials. J Antimicrob Chemother 71:913–915PubMed

29.

Liss B, Cornely OA, Hoffmann D, Dimitriou V, Wisplinghoff H (2016) 1,3-β-d-Glucan concentrations in blood products predict false positive post-transfusion results. Mycoses 59:39–42PubMed

30.

Egger M, Prüller F, Raggam R et al (2018) False positive serum levels of (1–3)-β-d-glucan after infusion of intravenous immunoglobulins and time to normalisation. J Infect 76:206–210PubMed

31.

Lo Cascio G, Koncan R, Stringari G et al (2015) Interference of confounding factors on the use of (1,3)-beta-d-glucan in the diagnosis of invasive candidiasis in the intensive care unit. Eur J Clin Microbiol Infect Dis 34:357–365PubMed

32.

Szyszkowitz A, Zurl C, Herzeg A et al (2018) Serum 1,3-beta-d-glucan values during and after laparoscopic and open intestinal surgery. Open Forum Infect Dis 5:ofy296PubMedPubMedCentral

33.

Ikemura K, Ikegami K, Shimazu T, Yoshioka T, Sugimoto T (1989) False-positive result in Limulus test caused by Limulus amebocyte lysate-reactive material in immunoglobulin products. J Clin Microbiol 27:1965–1968PubMedPubMedCentral

34.

Miura NN, Ohno N, Aketagawa J, Tamura H, Tanaka S, Yadomae T (1996) Blood clearance of (1 → 3)-beta-d-glucan in MRL lpr/lpr mice. FEMS Immunol Med Microbiol 13:51–57PubMed

35.

White SK, Schmidt RL, Walker BS, Hanson KE (2020) (1→3)-β-d-glucan testing for the detection of invasive fungal infections in immunocompromised or critically ill people. Cochrane Database Syst Rev 7:CD009833PubMed

36.

Otto GP, Ludewig K, Jacobsen ID, Schaarschmidt B, Hube B, Bauer M (2013) Limitation of (1 → 3)-β-d-Glucan monitoring in major elective surgery involving cardiopulmonary bypass. Crit Care 17:437PubMedPubMedCentral

37.

Mohr JF, Sims C, Paetznick V et al (2011) Prospective survey of (1 → 3)-beta-D-glucan and its relationship to invasive candidiasis in the surgical intensive care unit setting. J Clin Microbiol 49:58–61PubMed

38.

Martín-Mazuelos E, Loza A, Castro C et al (2015) β-d-Glucan and Candida albicans germ tube antibody in ICU patients with invasive candidiasis. Intensive Care Med 41:1424–1432PubMed

39.

Tissot F, Lamoth F, Hauser PM et al (2013) β-Glucan antigenemia anticipates diagnosis of blood culture-negative intraabdominal candidiasis. Am J Respir Crit Care Med 188:1100–1109PubMed

40.

Posteraro B, Tumbarello M, De Pascale G et al (2016) (1,3)-β-d-Glucan-based antifungal treatment in critically ill adults at high risk of candidaemia: an observational study. J Antimicrob Chemother 71:2262–2269PubMed

41.

León C, Ruiz-Santana S, Saavedra P et al (2016) Contribution of Candida biomarkers and DNA detection for the diagnosis of invasive candidiasis in ICU patients with severe abdominal conditions. Crit Care 20:149PubMedPubMedCentral

42.

Dupuis C, Le Bihan C, Maubon D et al (2021) Performance of repeated measures of (1–3)-β-d-glucan, mannan antigen, and antimannan antibodies for the diagnosis of invasive candidiasis in ICU patients: a preplanned ancillary analysis of the EMPIRICUS randomized clinical trial. Open Forum Infect Dis 8:ofab080PubMedPubMedCentral

43.

Klingspor L, Tortorano AM, Peman J et al (2015) Invasive Candida infections in surgical patients in intensive care units: a prospective, multicentre survey initiated by the European Confederation of Medical Mycology (ECMM) (2006–2008). Clin Microbiol Infect 21:87.e1-87.e10

44.

Alenazy H, Alghamdi A, Pinto R, Daneman N (2021) Candida colonization as a predictor of invasive candidiasis in non-neutropenic ICU patients with sepsis: a systematic review and meta-analysis. Int J Infect Dis 102:357–362PubMed

45.

León C, Ruiz-Santana S, Saavedra P et al (2009) Usefulness of the “Candida score” for discriminating between Candida colonization and invasive candidiasis in non-neutropenic critically ill patients: a prospective multicenter study. Crit Care Med 37:1624–1633PubMed

Title: (1 → 3)-β-d-Glucan-guided antifungal therapy in adults with sepsis: the CandiSep randomized clinical trial
Authors: Frank Bloos
Jürgen Held
Stefan Kluge
Philipp Simon
Klaus Kogelmann
Geraldine de Heer
Sven-Olaf Kuhn
Dominik Jarczak
Johann Motsch
Gunther Hempel
Norbert Weiler
Andreas Weyland
Matthias Drüner
Matthias Gründling
Patrick Meybohm
Daniel Richter
Ulrich Jaschinski
Onnen Moerer
Ulf Günther
Dirk Schädler
Raphael Weiss
Christian Putensen
Ixchel Castellanos
Oliver Kurzai
Peter Schlattmann
Oliver A. Cornely
Michael Bauer
Daniel Thomas-Rüddel
the SepNet Study Group
Publication date: 16-06-2022
Publisher: Springer Berlin Heidelberg
Keywords: Septicemia
Septicemia
Published in: Intensive Care Medicine / Issue 7/2022
Print ISSN: 0342-4642
Electronic ISSN: 1432-1238
DOI: https://doi.org/10.1007/s00134-022-06733-x

Keynote webinar | Spotlight on medication adherence

Springer Medicine

(1 → 3)-β-d-Glucan-guided antifungal therapy in adults with sepsis: the CandiSep randomized clinical trial

Abstract

Purpose

Methods

Results

Conclusions

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

Purpose

Methods

Results

Conclusions

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