A B-D-Glucan Driven Antifungal Stewardship Approach for Invasive Candidiasis

Study Overview
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Brief Summary
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This is a multicenter, prospective, open-label, randomized trial. Patients with severe abdominal condition developing severe sepsis or septic shock and receiving broad spectrum antibiotic and antifungal treatment will be randomized (1:1) to: discontinue antifungal treatment based on negative (<80 pg/ml) result of 1,3 beta-d-glucan performed on day 0,3,6 and 10 continue antifungal treatment according with attending physician's decision.

Detailed Description
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Primary objective: Our objective is to establish whether a strategy based on beta-d-glucan (BG) assessment could achieve reduced antifungal consumption in patients with severe abdominal condition developing severe sepsis and septic shock without any impact on the outcome Secondary objectives i) Assess the accuracy of BG in the diagnosis of invasive candidiasis (IC) in in critically ill patients with a severe abdominal condition who develop severe sepsis or septic shock. ii) Describe the changes over the time of BG value according with colonization status, infection or none the aforementioned events. Material and Methods Study design: a multicenter, open label, randomized trial Population: all the patients with a severe abdominal condition who develop a severe sepsis or septic shock. Inclusion Criteria: adult (≥ 18 year) patients; signed informed consent before surgical procedure; severe sepsis or septic shock; at least one of the following conditions: i) post-operative peritonitis, ii) recurrent gastrointestinal perforation, iii) post-operative hepatobiliary and/or pancreatic disorders including necrotizing pancreatitis, iv) post-operative intra-abdominal abscess, and v) anastomotic leak. Exclusion criteria a. diagnosis of candidiasis before the enrollment b. exposure in the past 30 days to any antifungal treatment or diagnosis of invasive fungal infection; c. pregnancy or lactation; d. history of allergy to any of the antifungal drugs; e. major immunosuppression conditions including: i. neutropenia (<0.5 × 109 neutrophils/L [<500 neutrophils/mm3] for >10 days), ii. receipt of an allogeneic stem cell transplant or solid organ transplantation, iii. inherited severe immunodeficiency (such as chronic granulomatous disease or severe combined immunodeficiency), iv. HIV infection with lymphocyte T CD4+ cell count < 200/mmc. f. patients with poor prognosis or unable to sign informed consent. Procedures Pre-randomization procedures At the time of patient enrollment (within 24 h from onset of severe sepsis/septic shock), a standardized diagnostic work-up must be performed including at least: i) two sets of blood cultures; ii) 5 surveillance cultures (rectal swab, urine culture, pharyngeal swab, axillary swab, groin swab). iii) in case of re-intervention or percutaneous drainage: Gram stain and culture of intra-abdominal samples; iv) serum BG determination. Antibiotic and antifungal empirical therapy should be started immediately after collection of microbiological samples according with a predefined standard of care (see appendix 1). Once completed this procedures patients will proceed to randomization. Randomization Patient eligible for the study after the beginning of antifungal therapy will be randomized 1:1 to receive (Group A) a BG driven de-escalation strategy or (Group B) a course of antifungal treatment based on the care provider's decision. In both groups, if cultures yield invasive candidiasis (see below) the patient will be managed in according with guidelines and excluded from the per-protocol analysis. In both groups, BG determination will be repeated at day +3, +6 and +10 after starting antifungal therapy. Randomization will be carried out providing closed envelopes to the participating centers immediately before the study onset.

Official Title
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A B-D-Glucan Driven Antifungal Stewardship Approach to Manage Empirical Therapy in Patients at Very High Risk for Invasive Candidiasis: a Randomized Controlled Trial

Conditions
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Invasive Candidiases, Abdominal Infection

Intervention / Treatment
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* Diagnostic Test: De-escalation


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: a. adult (≥ 18 year) patients; b. signed informed consent before surgical procedure; c. severe sepsis or septic shock; d. at least one of the following conditions: i) post-operative peritonitis, ii) recurrent gastrointestinal perforation, iii) post-operative hepatobiliary and/or pancreatic disorders including necrotizing pancreatitis, iv) post-operative intra-abdominal abscess, and v) anastomotic leak. Exclusion Criteria: a. diagnosis of candidiasis before the enrollment b. exposure in the past 30 days to any antifungal treatment or diagnosis of invasive fungal infection; c. pregnancy or lactation; d. history of allergy to any of the antifungal drugs; e. major immunosuppression conditions including: i. neutropenia (<0.5 × 109 neutrophils/L [<500 neutrophils/mm3] for >10 days), ii. receipt of an allogeneic stem cell transplant or solid organ transplantation, iii. inherited severe immunodeficiency (such as chronic granulomatous disease or severe combined immunodeficiency), iv. HIV infection with lymphocyte T CD4+ cell count < 200/mmc. f. patients with poor prognosis or unable to sign informed consent.

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: Other
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: De-escalation<br>In this group, investigators will manage the antifungal therapy according to the BG levels as follows: antifungal therapy will be stopped immediately after the BG response in case of serum BG <80 pg/ml in presence of clinical stability (CS); antifungal therapy will be continued until further BG determination, both for BG levels between 80-200 pg/ml and for BG <80 pg/ml in patients without CS. In these cases, if the following BG value is <80 pg/ml antifungal therapy will be stopped independently from the CS achievement. antifungal therapy will be continued until day 10 for BG levels >200 pg/ml | Diagnostic Test: De-escalation<br>* Antifungal therapy will be stopped according with BG results<br>|
| No Intervention: Standard of care<br>In this group antifungal treatment will be continued until clinician's decision. Investigators will be blinded to the BG levels of patients enrolled in this arm, The BG results will be faxed directly to the coordinating center. | |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Antifungal consumption | Days of antifungal consumption will be compared between the two groups | 28 days | 
| Mortality | 28-day mortality will be compared between the two groups | 28 days | 
| Length of stay | Length of stay in ICU will be compared between the two groups | 28 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Accuracy of BG | sensitivity, specificity, positive predictive value, negative predictive value of BG in the diagnosis of invasive candidiasis | 28 days | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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beta-d-glucan, abdominal candidiasis