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Study of Innate Host Immune Response to C. Glabrata Clinical Isolates Resistant to Echinocandins: Impact on the Management of Candidemia in High-risk Patients (CAHOHR)

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ClinicalTrials.gov Identifier: NCT03652194
Recruitment Status : Active, not recruiting
First Posted : August 29, 2018
Last Update Posted : August 29, 2018
Sponsor:
Information provided by (Responsible Party):
Centre Hospitalier Universitaire Dijon

Brief Summary:

In the context of Candida yeast infections, a large number of studies have been published over the past two decades specifying the molecular mechanisms of antifungal resistance in different Candida species. However, few of these studies have explored how these mechanisms influence host immune response to this opportunistic pathogen. Recent advances in understanding how the host's immune system responds to Candida have initiated the emergence of a new research theme aimed at better understanding Candida's intrinsic and adaptive resistance mechanisms to antifungals can modulate "escape to" or "recognition by" the host's immune system. This knowledge could lead to (i) a better understanding of the predominance of certain Candida species with antifungal resistance in certain patient populations, (ii) a better understanding of why high levels of in vitro resistance are not necessarily correlated with in vivo therapeutic failure, and (iii) effective immunotherapeutic strategies to control Candida resistance to antifungals.

It is therefore crucial to investigate the impact of Candida's resistance to antifungals on the host's innate immune response. Indeed, most antifungal resistance mechanisms have a direct or indirect structural modification of the fungal wall. However, it is the composition of this wall that is involved in the recognition of Candida by the host cell via the pattern recognition receptors (PRRs). We therefore put forward the very probable hypothesis that changes in the fungal wall, induced by the appearance of resistance, could alter the recognition of Candida by PRRs and thus trigger a different immune response, either qualitatively (type of cytokines secreted) or quantitatively (amplitude and duration of the immune response). However, even if initial experimental data support the hypothesis of a possible link between resistance and a modulation of the innate immune response in digestive mucosa (the most frequent starting point for disseminated candidiasis), many questions remain regarding (i) the proteins and mechanisms of the modulated immune cascade, (ii) the modification of the immune response according to the Candida species in question and (iii) the modification of the immune response according to the resistance phenotype in question.


Condition or disease Intervention/treatment
Candidemia of C. Glabrata Other: in vitro evaluation of epithelial immune response during C. glabrata infection Other: study of the impact of resistance phenotype acquisition on the virulence of C. glabrata isolates

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Study Type : Observational
Actual Enrollment : 21 participants
Observational Model: Cohort
Time Perspective: Other
Official Title: Study of Innate Host Immune Response to C. Glabrata Clinical Isolates Resistant to Echinocandins: Impact on the Management of Candidemia in High-risk Patients
Actual Study Start Date : January 1, 2018
Estimated Primary Completion Date : January 2019
Estimated Study Completion Date : June 2019

Resource links provided by the National Library of Medicine


Group/Cohort Intervention/treatment
Reference strain ATCC
1 strain sensitive to all antifungals
Other: in vitro evaluation of epithelial immune response during C. glabrata infection
  1. study of the expression of genes coding for different proteins involved in the RTqPCR activation cascade
  2. study of protein expression by the Western-Blot method

Other: study of the impact of resistance phenotype acquisition on the virulence of C. glabrata isolates
  1. in vitro evaluation by measuring cell invasion, cell adhesion and by determining epithelial cell cytotoxicity.
  2. in vivo evaluation measured by a survival study on a CD-1 mouse model.

Clinical isolates sensitive to all antifungal agents
10 clinical isolates sensitive to all
Other: in vitro evaluation of epithelial immune response during C. glabrata infection
  1. study of the expression of genes coding for different proteins involved in the RTqPCR activation cascade
  2. study of protein expression by the Western-Blot method

Other: study of the impact of resistance phenotype acquisition on the virulence of C. glabrata isolates
  1. in vitro evaluation by measuring cell invasion, cell adhesion and by determining epithelial cell cytotoxicity.
  2. in vivo evaluation measured by a survival study on a CD-1 mouse model.

Echinocandin-resistant clinical isolates
10 echinocandin-resistant clinical isolates (Eucast, Caspofungin > 8µg/ml)
Other: in vitro evaluation of epithelial immune response during C. glabrata infection
  1. study of the expression of genes coding for different proteins involved in the RTqPCR activation cascade
  2. study of protein expression by the Western-Blot method

Other: study of the impact of resistance phenotype acquisition on the virulence of C. glabrata isolates
  1. in vitro evaluation by measuring cell invasion, cell adhesion and by determining epithelial cell cytotoxicity.
  2. in vivo evaluation measured by a survival study on a CD-1 mouse model.




Primary Outcome Measures :
  1. Quantification of accession and invasion [ Time Frame: Baseline ]
    In vitro study of different virulence markers

  2. Test SytoxOrange [ Time Frame: Baseline ]
    In vitro study of different cytotoxicity markers in digestive epithelial cells

  3. Quantification of the gene expression of the various cytokines associated with the immune response in digestive epithelial cells. [ Time Frame: Baseline ]


Information from the National Library of Medicine

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Ages Eligible for Study:   Child, Adult, Older Adult
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Sampling Method:   Non-Probability Sample
Study Population
Collection from the "multicentric study of Echinocandin-resistance in Candida glabrata candidemia" (multicentre retrospective study on a cohort of 172 patients managed for a C. glabrata cadidemia between 2013 and 2015).
Criteria

Inclusion Criteria:

  • 10 clinical isolates sensitive to all antifungal agents
  • 10 echinocandin-resistant clinical isolates (Eucast, caspofungin > 8µg/ml)

Clinical strains of C. glabrata susceptible or resistant to echinocandins will be selected on selected criteria:

  • patient's immune status
  • therapeutic management
  • clinical developments

Exclusion Criteria:

  • Not applicable

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03652194


Locations
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France
Chu Dijon Bourogne
Dijon, France, 21000
Sponsors and Collaborators
Centre Hospitalier Universitaire Dijon

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Responsible Party: Centre Hospitalier Universitaire Dijon
ClinicalTrials.gov Identifier: NCT03652194    
Other Study ID Numbers: Basmaciyan AOI 2017
First Posted: August 29, 2018    Key Record Dates
Last Update Posted: August 29, 2018
Last Verified: August 2018

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Additional relevant MeSH terms:
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Candidemia
Fungemia
Sepsis
Infection
Candidiasis, Invasive
Candidiasis
Mycoses
Invasive Fungal Infections
Systemic Inflammatory Response Syndrome
Inflammation
Pathologic Processes
Echinocandins
Antifungal Agents
Anti-Infective Agents