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

Abdominal Infection Clinical Trial

Official title:

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

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT03090334
• Other study ID #: BDG-ETHIC
• Status: Recruiting
• Phase: N/A
• Start date: March 1, 2017
• Est. completion date: December 2020

Study information

• Verified date: April 2019
• Source: University of Bologna
• Contact: Maddalena Giannella, MD, phD
• Phone: +39 0512143199
• Email: maddalena.giannella[@]unibo.it
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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:

1. discontinue antifungal treatment based on negative (<80 pg/ml) result of 1,3 beta-d-glucan performed on day 0,3,6 and 10

2. continue antifungal treatment according with attending physician's decision.

Description:

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.

1. Inclusion Criteria:

1. adult (≥ 18 year) patients;

2. signed informed consent before surgical procedure;

3. severe sepsis or septic shock;

4. 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.

2. 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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 180
• Est. completion date: December 2020
• Est. primary completion date: June 2020
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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.

Related Conditions & MeSH terms

• Abdominal Infection
• Candidiasis
• Candidiasis, Invasive
• Intraabdominal Infections
• Invasive Candidiases

Intervention

Diagnostic Test:
• De-escalation
Antifungal therapy will be stopped according with BG results

Locations

Country	Name	City	State
Italy	Azienda Ospealiero Universitaria di Bologna Policlinico S.Orsola-Malpighi	Bologna

Sponsors (1)

Lead Sponsor	Collaborator
University of Bologna

Country where clinical trial is conducted

Italy, 

References & Publications (4)

Bassetti M, Marchetti M, Chakrabarti A, Colizza S, Garnacho-Montero J, Kett DH, Munoz P, Cristini F, Andoniadou A, Viale P, Rocca GD, Roilides E, Sganga G, Walsh TJ, Tascini C, Tumbarello M, Menichetti F, Righi E, Eckmann C, Viscoli C, Shorr AF, Leroy O, Petrikos G, De Rosa FG. A research agenda on the management of intra-abdominal candidiasis: results from a consensus of multinational experts. Intensive Care Med. 2013 Dec;39(12):2092-106. doi: 10.1007/s00134-013-3109-3. Epub 2013 Oct 9. — View Citation

Clancy CJ, Nguyen MH. Finding the "missing 50%" of invasive candidiasis: how nonculture diagnostics will improve understanding of disease spectrum and transform patient care. Clin Infect Dis. 2013 May;56(9):1284-92. doi: 10.1093/cid/cit006. Epub 2013 Jan 11. Review. — View Citation

Kollef M, Micek S, Hampton N, Doherty JA, Kumar A. Septic shock attributed to Candida infection: importance of empiric therapy and source control. Clin Infect Dis. 2012 Jun;54(12):1739-46. doi: 10.1093/cid/cis305. Epub 2012 Mar 15. — View Citation

Maubon D, Garnaud C, Calandra T, Sanglard D, Cornet M. Resistance of Candida spp. to antifungal drugs in the ICU: where are we now? Intensive Care Med. 2014 Sep;40(9):1241-55. doi: 10.1007/s00134-014-3404-7. Epub 2014 Aug 5. Review. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Antifungal consumption	Days of antifungal consumption will be compared between the two groups	28 days
Primary	Mortality	28-day mortality will be compared between the two groups	28 days
Primary	Length of stay	Length of stay in ICU will be compared between the two groups	28 days
Secondary	Accuracy of BG	sensitivity, specificity, positive predictive value, negative predictive value of BG in the diagnosis of invasive candidiasis	28 days