Early Discontinuation of Empirical Antifungal Therapy and Biomarkers

Study Overview
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Brief Summary
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Empirical antifungal therapy (EAT) is frequently prescribed to septic critically ill patients with risk factors for invasive Candida infections (ICI). However, among patients without subsequent proven ICI, antifungal discontinuation is rarely performed, resulting in unnecessary antifungal overuse. The investigators postulate that the use of fungal biomarkers could increase the percentage of early discontinuation of EAT among critically ill patients suspected of ICI, as compared with a standard strategy, without negative impact on day 28-mortality. To test this hypothesis, the investigators designed a randomized controlled open-label parallel-group study.

Detailed Description
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Patients requiring EAT will be randomly assigned to: intervention group: a strategy in which EAT duration is determined by (1,3)-B-Dglucan and mannan serum assays, performed on day 0 (day of EAT initiation) and day 3. Early stop recommendation, provided before day 7, will be determined using an algorithm based on the results of biomarkers. control group: a routine care strategy, based on international guidelines, which recommend 14 days of treatment for patients without subsequent proven ICI, and who improve under antifungal treatment, or less in other situations.

Official Title
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Impact of the Use of Biomarkers on Early Discontinuation of Empirical Antifungal Therapy in Critically Ill Patients: a Randomized Controlled Study.

Conditions
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Invasive Candidiasis

Intervention / Treatment
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* Other: Biomarker strategy
* Other: Routine strategy


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patient older than 18 years Who require EAT for the first time in the ICU (this treatment is prescribed based on the presence of risk factors and clinical suspicion of ICI) With an expected ICU length of stay of at least 6 days after EAT initiation Informed written consent Exclusion Criteria: Neutropenia (neutrophil count <500 cells /µL) Active malignant hemopathy Bone marrow transplantation in the last 6 months Polyvalent immunoglobulins in the past months Documented ICI in the past 3 months Pregnancy or breastfeeding

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Other: Biomarker group<br>patient follow the Biomarker strategy | Other: Biomarker strategy<br>* EAT duration is determined by β-D-1,3-glucan and mannan serum assays, performed at day 0 (day of EAT initiation) and day 3.<br>|
| Other: Routine group<br>patient follow the routine strategy | Other: Routine strategy<br>* EAT duration is based on IDSA guidelines, which recommend 14 days of treatment for patients without subsequent proven ICI, and who improve under antifungal treatment, or less in other situations.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| percentage of patients receiving early discontinuation of EAT, defined as a discontinuation strictly before day 7 after EAT initiation | This trial is designed to demonstrate whether, in critically ill patients suspected for ICI, the biomarker strategy, as compared with a standard strategy, is at the same time: superior in terms of antifungal use and Non-inferior in terms of death | day 7 after EAT initiation | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| death from any cause | This trial is designed to demonstrate whether, in critically ill patients suspected for ICI, the biomarker strategy, as compared with a standard strategy, is at the same time: superior in terms of antifungal use and Non-inferior in terms of death | day 28 after EAT initiation | 
| percentage of patients who presented a proven ICI after EAT discontinuation |  | at day 28 or ICU discharge, if it occurs before day 28 | 
| percentage of patients who received at least two periods of antifungal treatment (prescribed for separate episodes of suspected or proven ICI) |  | at day 28 or ICU discharge, if it occurs before day 28 | 
| intensity of Candida colonization during ICU stay | Five body sites (among urine, anal swabs, pharyngeal swabs, nasal swabs, axillary swabs, gastric aspirates if patients have a nasogastric tube, and tracheal aspirates if patients are intubated or have a tracheotomy) are sampled on day 0 and then once per week for the semi-quantitative determination of yeast colonisation. The number of colony-forming units is scored as follows: score 1, <10 colony-forming units; score 2, 10 to 50 colony-forming units; score 3, >50 colony-forming units; score 4, >50 colony-forming units confluent. Intensity of colonization is determined for each date of sampling, by dividing the sum score for each colonized site by the number of sites sampled giving a mean Candida load. An overall score of >4 is possible in the case of isolation of several Candida species. | at day 28 or ICU discharge, if it occurs before day 28 | 
| percentage of patients colonized with a resistant strain of Candida |  | at day 28 or ICU discharge, if it occurs before day 28 | 
| antifungal-free days |  | at day 28 or ICU discharge, if it occurs before day 28 | 
| ventilator-free days |  | at day 28 or ICU discharge, if it occurs before day 28 | 
| ICU-free days |  | at day 28 or ICU discharge, if it occurs before day 28 | 
| ICU mortality |  | at day 28 or ICU discharge, if it occurs before day 28 | 
| day 90 mortality |  | at day 90 | 
| Characterization of the fungal intestinal microbiota studied by standard mycology |  | at baseline, at Day 7, day 14 day 21 and day 28 | 
| Characterization of the fungal intestinal microbiota studied by metagenomics |  | at baseline, at Day 7, day 14 day 21 and day 28 | 
| Characterization of the bacterial intestinal microbiota studied by culture bacteriology |  | at baseline, at Day 7, day 14 day 21 and day 28 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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biomarkers, empirical antifungal therapy, invasive candidiasis, de-escalation, ICU