(1,3)-β-D-Glucan-based empirical antifungal interruption in suspected invasive candidiasis: a randomized trial

Gennaro De Pascale, Brunella Posteraro, Sonia D'Arrigo, Giorgia Spinazzola, Rita Gaspari, Giuseppe Bello, Luca Maria Montini, Salvatore Lucio Cutuli, Domenico Luca Grieco, Valentina Di Gravio, Giulia De Angelis, Riccardo Torelli, Elena De Carolis, Mario Tumbarello, Maurizio Sanguinetti, Massimo Antonelli, Gennaro De Pascale, Brunella Posteraro, Sonia D'Arrigo, Giorgia Spinazzola, Rita Gaspari, Giuseppe Bello, Luca Maria Montini, Salvatore Lucio Cutuli, Domenico Luca Grieco, Valentina Di Gravio, Giulia De Angelis, Riccardo Torelli, Elena De Carolis, Mario Tumbarello, Maurizio Sanguinetti, Massimo Antonelli

Abstract

Background: (1,3)-β-D-Glucan has been widely used in clinical practice for the diagnosis of invasive Candida infections. However, such serum biomarker showed potential to guide antimicrobial therapy in order to reduce the duration of empirical antifungal treatment in critically ill septic patients with suspected invasive candidiasis.

Methods: This was a single-centre, randomized, open-label clinical trial in which critically ill patients were enrolled during the admission to the intensive care unit (ICU). All septic patients who presented invasive Candida infection risk factors and for whom an empirical antifungal therapy was commenced were randomly assigned (1:1) in those stopping antifungal therapy if (1,3)-β-D-glucan was negative ((1,3)-β-D-glucan group) or those continuing the antifungal therapy based on clinical rules (control group). Serum 1,3-β-D-glucan was measured at the enrolment and every 48/72 h over 14 days afterwards. The primary endpoint was the duration of antifungal treatment in the first 30 days after enrolment.

Results: We randomized 108 patients into the (1,3)-β-D-glucan (n = 53) and control (n = 55) groups. Median [IQR] duration of antifungal treatment was 2 days [1-3] in the (1,3)-β-D-glucan group vs. 10 days [6-13] in the control group (between-group absolute difference in means, 6.29 days [95% CI 3.94-8.65], p < 0.001). Thirty-day mortality was similar (28.3% [(1,3)-β-D-glucan group] vs. 27.3% [control group], p = 0.92) as well as the overall rate of documented candidiasis (11.3% [(1,3)-β-D-glucan group] vs. 12.7% [control group], p = 0.94), the length of mechanical ventilation (p = 0.97) and ICU stay (p = 0.23).

Conclusions: In critically ill septic patients admitted to the ICU at risk of invasive candidiasis, a (1,3)-β-D-glucan-guided strategy could reduce the duration of empirical antifungal therapy. However, the safety of this algorithm needs to be confirmed in future, multicentre clinical trial with a larger population.

Trial registration: ClinicalTrials.gov, NCT03117439 , retrospectively registered on 18 April 2017.

Keywords: (1,3)-β-D-Glucan; Antifungal therapy; Biomarker; Candida infection; Sepsis.

Conflict of interest statement

None declared.

Figures

Fig. 1
Fig. 1
Flow chart of the study inclusion process
Fig. 2
Fig. 2
a Kaplan-Meier plots showing the evolution with time of the percentage of patients who remained on antifungals in the (1,3)-β-d-glucan and control groups. b Probability of survival from study inclusion (day 0) through day 30 for patients in the (1,3)-β-d-glucan and control groups
Fig. 3
Fig. 3
a (1,3)-β-d-Glucan results for patients with and without invasive Candida infections. b Duration of antifungal therapy among intensive care unit patients according to the absence or presence of invasive Candida infections and the positivity of the (1,3)-β-d-glucan assay

References

    1. Ostrosky-Zeichner L, Shoham S, Vazquez J, Reboli A, Betts R, Barron M, Schuster M, Judson M, Revankar S, Caeiro J, et al. 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. 2014;58(9):1219–1226.
    1. León C, Ruiz-Santana S, Saavedra P, Almirante B, Nolla-Salas J, Alvarez-Lerma F, Garnacho-Montero J, León M, EPCAN Study Group A bedside scoring system (“Candida score”) for early antifungal treatment in nonneutropenic critically ill patients with Candida colonization. Crit Care Med. 2006;34(3):730–737.
    1. León C, Ruiz-Santana S, Saavedra P, Galván B, Blanco A, Castro C, Balasini C, Utande-Vázquez A, González de Molina F, Blasco-Navalproto M, et al. 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. 2009;37(5):1624–1633.
    1. Pittet D, Monod M, Suter P, Frenk E, Auckenthaler R. Candida colonization and subsequent infections in critically ill surgical patients. Ann Surg. 1994;220(6):751–758.
    1. Eggimann P, Pittet D. Candida colonization index and subsequent infection in critically ill surgical patients: 20 years later. Intensive Care Med. 2014;40(10):1429–1448.
    1. Martin-Loeches I, Antonelli M, Cuenca-Estrella M, Dimopoulos G, Einav S, De Waele J, Garnacho-Montero J, Kanj S, Machado F, Montravers P, et al. ESICM/ESCMID task force on practical management of invasive candidiasis in critically ill patients. Intensive Care Med. 2019;45(6):789–805.
    1. Pappas P, Kauffman C, Andes D, Clancy C, Marr K, Ostrosky-Zeichner L, Reboli A, Schuster M, Vazquez J, Walsh T, et al. Executive summary: clinical practice guideline for the management of candidiasis: 2016 update by the Infectious Diseases Society of America. Clin Infect Dis. 2016;62(4):409–417.
    1. Azoulay E, Dupont H, Tabah A, Lortholary O, Stahl J, Francais A, Martin C, Guidet B, Timsit J. Systemic antifungal therapy in critically ill patients without invasive fungal infection*. Crit Care Med. 2012;40(3):813–822.
    1. Timsit J, Azoulay E, Schwebel C, Charles P, Cornet M, Souweine B, Klouche K, Jaber S, Trouillet J, Bruneel F, et al. 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. 2016;316(15):1555–1564.
    1. Jaffal K, Poissy J, Rouze A, Preau S, Sendid B, Cornu M, Nseir S. De-escalation of antifungal treatment in critically ill patients with suspected invasive Candida infection: incidence, associated factors, and safety. Ann Intensive Care. 2018;8(1):49.
    1. Poissy J, Sendid B, Damiens S, Ishibashi KI, François N, Kauv M, Favory R, Mathieu D, Poulain D. Presence of Candida cell wall derived polysaccharides in the sera of intensive care unit patients: relation with candidaemia and Candida colonisation. Crit Care. 2014;18(3):R135.
    1. Hanson K, Pfeiffer C, Lease E, Balch A, Zaas A, Perfect J, Alexander B. β-D-glucan surveillance with preemptive anidulafungin for invasive candidiasis in intensive care unit patients: a randomized pilot study. PLoS One. 2012;7(8):e42282.
    1. Nucci M, Nouér S, Esteves P, Guimarães T, Breda G, de Miranda B, Queiroz-Telles F, Colombo A. Discontinuation of empirical antifungal therapy in ICU patients using 1,3-β-d-glucan. J Antimicrob Chemother. 2016;71(9):2628–2633.
    1. Martín-Mazuelos E, Loza A, Castro C, Macías D, Zakariya I, Saavedra P, Ruiz-Santana S, Marín E, León C. β-D-Glucan and Candida albicans germ tube antibody in ICU patients with invasive candidiasis. Intensive Care Med. 2015;41(8):1424–1432.
    1. Rautemaa-Richardson R, Rautemaa V, Al-Wathiqi F, Moore C, Craig L, Felton T, Muldoon E. Impact of a diagnostics-driven antifungal stewardship programme in a UK tertiary referral teaching hospital. J Antimicrob Chemother. 2018;73(12):3488–3495.
    1. Rouzé A, Loridant S, Poissy J, Dervaux B, Sendid B, Cornu M, Nseir S. S-TAFE study group: biomarker-based strategy for early discontinuation of empirical antifungal treatment in critically ill patients: a randomized controlled trial. Intensive Care Med. 2017;43(11):1668–1677.
    1. Posteraro B, De Pascale G, Tumbarello M, Torelli R, Pennisi M, Bello G, Maviglia R, Fadda G, Sanguinetti M, Antonelli M. Early diagnosis of candidemia in intensive care unit patients with sepsis: a prospective comparison of (1→3)-β-D-glucan assay, Candida score, and colonization index. Crit Care. 2011;15(5):R249.
    1. Posteraro B, Tumbarello M, De Pascale G, Liberto E, Vallecoccia M, De Carolis E, Di Gravio V, Trecarichi E, Sanguinetti M, Antonelli M. (1,3)-β-d-Glucan-based antifungal treatment in critically ill adults at high risk of candidaemia: an observational study. J Antimicrob Chemother. 2016;71(8):2262–2269.
    1. Singer M, Deutschman C, Seymour C, Shankar-Hari M, Annane D, Bauer M, Bellomo R, Bernard G, Chiche J, Coopersmith C, et al. The third international consensus definitions for sepsis and septic shock (Sepsis-3) JAMA. 2016;315(8):801–810.
    1. Rhodes A, Evans L, Alhazzani W, Levy M, Antonelli M, Ferrer R, Kumar A, Sevransky J, Sprung C, Nunnally M, et al. Surviving sepsis campaign: international guidelines for management of sepsis and septic shock: 2016. Intensive Care Med. 2017;43(3):304–377.
    1. Colombo A, de Almeida JJ, Slavin M, Chen S, Sorrell T. Candida and invasive mould diseases in non-neutropenic critically ill patients and patients with haematological cancer. Lancet Infect Dis. 2017;17(1):e344–e356.
    1. Giacobbe D, Mikulska M, Tumbarello M, Furfaro E, Spadaro M, Losito A, Mesini A, De Pascale G, Marchese A, Bruzzone M, et al. Combined use of serum (1,3)-β-D-glucan and procalcitonin for the early differential diagnosis between candidaemia and bacteraemia in intensive care units. Crit Care. 2017;21(1):176.
    1. Tissot F, Lamoth F, Hauser P, Orasch C, Flückiger U, Siegemund M, Zimmerli S, Calandra T, Bille J, Eggimann P, et al. β-Glucan antigenemia anticipates diagnosis of blood culture-negative intraabdominal candidiasis. Am J Respir Crit Care Med. 2013;188(9):1100–1109.
    1. Martínez-Jiménez M, Muñoz P, Valerio M, Alonso R, Martos C, Guinea J, Bouza E. Candida biomarkers in patients with candidaemia and bacteraemia. J Antimicrob Chemother. 2015;70(8):2354–2361.
    1. Bailly S, Bouadma L, Azoulay E, Orgeas M, Adrie C, Souweine B, Schwebel C, Maubon D, Hamidfar-Roy R, Darmon M, et al. Failure of empirical systemic antifungal therapy in mechanically ventilated critically ill patients. Am J Respir Crit Care Med. 2015;191(10):1139–1146.
    1. Leroy O, Bailly S, Gangneux J, Mira J, Devos P, Dupont H, Montravers P, Perrigault P, Constantin J, Guillemot D, et al. Systemic antifungal therapy for proven or suspected invasive candidiasis: the AmarCAND 2 study. Ann Intensive Care. 2016;6(1):2.
    1. Tabah A, Cotta M, Garnacho-Montero J, Schouten J, Roberts J, Lipman J, Tacey M, Timsit J, Leone M, Zahar J, et al. A systematic review of the definitions, determinants, and clinical outcomes of antimicrobial de-escalation in the intensive care unit. Clin Infect Dis. 2016;62(8):1009–1017.
    1. Liss B, Cornely O, Hoffmann D, Dimitriou V, Wisplinghoff H. 1,3-ß-D-glucan concentrations in blood products predict false positive post-transfusion results. Mycoses. 2016;59(1):39–42.
    1. Liss B, Cornely O, Hoffmann D, Dimitriou V, Wisplinghoff H. 1,3-β-D-Glucan contamination of common antimicrobials. J Antimicrob Chemother. 2016;71(4):913–915.
    1. Bailly S, Leroy O, Azoulay E, Montravers P, Constantin J, Dupont H, Guillemot D, Lortholary O, Mira J, Perrigault P, et al. Impact of echinocandin on prognosis of proven invasive candidiasis in ICU: a post-hoc causal inference model using the AmarCAND2 study. J Inf Secur. 2017;74(4):408–417.
    1. Urbancic K, Thursky K, Kong D, Johnson P, Slavin M. Antifungal stewardship: developments in the field. Curr Opin Infect Dis. 2018;31(6):490–498.

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