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Randomized Controlled Trial
. 2023 Nov 15;67(11):e0072523.
doi: 10.1128/aac.00725-23. Epub 2023 Oct 12.

β-(1→3)-D-glucan- and mannan-guided early termination of antifungal therapy in ICU patients: a randomized controlled study

Timothy Erb  1 , Sidonia Mihai  2 , Richard Strauß  3 , Larissa Herbst  4 , Ixchel Castellanos  5 , Katharina Diesch  6 , Franziska Cipa  2 , Karl Bihlmaier  4 , Anne-Katharina Lang  5 , Marion Ganslmayer  3 , Carsten Willam  4 , Frank Bremer  5 , Julia Fürst  3 , Christian Beyer  3 , Christian Bogdan  1 , Anca Rath  1 , Jürgen Held  1
Affiliations
Randomized Controlled Trial

β-(1→3)-D-glucan- and mannan-guided early termination of antifungal therapy in ICU patients: a randomized controlled study

Timothy Erb et al. Antimicrob Agents Chemother. .

Abstract

Candida spp. are frequently encountered in specimens from ICUs. However, most of these detections represent colonization. Nevertheless, clinical practice shows that a considerable proportion of these patients will receive antifungal therapy (AT). β-(1→3)-D-glucan (BDG) and mannan are fungal biomarkers with high negative predictive values. We aimed to examine whether biomarker-guided discontinuation of AT can reduce the antifungal consumption. Therefore, we conducted a prospective, randomized intervention study between 1 April 2019 and 31 March 2020. All adult ICU patients with a newly started systemic AT but without fungal infection were eligible for inclusion. Enrolled patients were randomized into an intervention and a control group. In both groups, serum BDG and mannan were determined on days 1 and 2 of AT. If all measurements were negative, AT was discontinued in the intervention group. The primary endpoint was antifungal use. The study was terminated after 12 months. Until this time-point, 41 patients had been included. In the intervention group (n = 19), AT was stopped in only two patients because all others showed either positive BDG and/or mannan levels. One of these two patients developed candidemia and AT had to be restarted. There was no significant difference in the primary and secondary endpoints. In summary, the strategy of using two negative BDG and mannan levels to stop AT failed to reduce antifungal consumption in our cohort. Indeed, there will inevitably be patients with invasive candidiasis in whom necessary AT is discontinued. The optimal patient population, biomarker set, and termination criteria are critical to the success of biomarker-based termination strategies.

Keywords: Candida infection; antibiotic stewardship; antifungal therapy; biomarker; candidemia; candidosis; discontinuation; fungal infection.

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Conflict of interest statement

J.H. received honoraria for conference talks from Pfizer Pharma GmbH, Gilead Sciences GmbH and Associates of Cape Cod, Inc. and kits for the detection of BDG free of charge for other studies from Associates of Cape Cod, Inc. and from FUJIFILM Wako Chemicals Europe GmbH. None of these companies funded the present study. All other authors declare that they have no financial or ethical conflicts of interest regarding the contents of the publication. Potential conflicts of interest for RS (since 2019) Honoraria as a member of advisory boards from Biotest, Gilead Sciences, GlaxoSmithKline Honoraria for lectures at medical training courses or conference talks from Amomed- Pharmaceuticals, Biotest, CSL Behring, Gilead Sciences, Infectopharm, MSD (Merck Sharp & Dohme), Pfizer-Pharma, Shionogi, Tillotts-Pharma consultancies, stock or equity interests, and patent-licensing arrangements. No grant for the present study.

Figures

Fig 1
Fig 1
CONSORT 2010 participant flow diagram.
Fig 2
Fig 2
Biomarker kinetics of a patient with candidemia in whom antifungal therapy was stopped. Antifungal therapy was stopped on day 2. Mannan and BDG became positive on days 3 and 4, respectively. The red and black dotted lines depict the cut-off values for mannan and BDG. F, fluconazole; BDG, β-(1→3)-D-glucan.
See this image and copyright information in PMC

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