AssessmeNT of the Incidence of Clostridium Difficile Infections in Hospitalized Patients on Antibiotic TrEatment (ANTICIPATE)

During or after antibiotic treatment, antibiotic residues impair the intestinal microbiota (gut flora) and lead to adverse effects such as the emergence of bacterial resistance or the occurrence antibiotic-associated diarrhoea (AAD) including antibiotic-induced C. difficile infection (CDI). The spread of resistant Gram-negative bacteria and the increasing number and severity of CDI are considered as worldwide public health threats.

Da Volterra is a biotechnology company developing a novel product, DAV132 (a medical device in Europe), intended to prevent these antibiotic adverse effects. Da Volterra is planning to carry out a phase 2-3 randomized controlled trial (RCT) of DAV132 in the prevention of antibiotic-induced CDI. The RCT will involve hospitalized patients aged ≥50 years old and treated with predefined antibiotic classes known to increase the risk of CDI. The incidence of CDI in this population is unknown, yet, incidence is an important determinant for the required sample size.

Therefore, the main objective of the current study is to assess CDI incidence in patients ≥50 years of age treated with predefined antibiotic classes.

In addition, to optimise the target population of the DAV132 RCT, the effect of the predefined antibiotic agents on the intestinal microbiota will be assessed. Furthermore, biomarkers predictive of CDI occurrence might help identify patients at high risk for the disease, which could further optimise the RCT. No validated biomarkers have been described in the literature yet. Assessment of potential biomarkers is another aim of the present study.

Study Overview

• Status: Completed
• Conditions: Clostridium Difficile
• Intervention / Treatment: Other: no intervention

• Study Type: Observational
• Enrollment (Actual): 1007

Contacts and Locations

Study Locations

• France
  • La Roche-sur-Yon, France
    • CHD Vendée
  • Limoges, France
    • CHU Dupuytren
  • Paris, France
    • APHP Bichat
  • Paris, France
    • APHP Hôpital Cochin
  • Paris, France
    • Hôpital St Louis
  • Paris, France
    • APHP Beaujon
  • Quimper, France
    • CH de Cornouaille
  • Tours, France
    • Centre Hospitalier Universitaire de Tours
• Germany
  • Aachen, Germany
    • Uniklinik der RWTH
  • Cologne, Germany
    • Uniklinik Köln
  • Essen, Germany
    • Universitatsklinikum Essen
  • Heidelberg, Germany
    • Universitätsklinikum Heidelberg
  • Jena, Germany
    • Universitatsklinikum Jena
  • Leipzig, Germany
    • UK Leipzig
  • Lübeck, Germany
    • Universitätsklinikum Schleswig-Holstein, Lübeck
  • Munchen, Germany
    • Klinikum der Universität München
• Greece
  • Athens, Greece
    • Laiko General Hospital
  • Athens, Greece
    • Evangelismos General Hospital of Athens
  • Athens, Greece
    • Ippokratio Hospital of Athens
  • Athens, Greece
    • University General Hospital ATTIKON
  • Iráklion, Greece
    • University Hospital of Heraklion
• Netherlands
  • Utrecht, Netherlands
    • University Medical Center
• Romania
  • Bucharest, Romania
    • Infectious and Tropical Diseases Hospital "Dr. Victor Babes"
  • Bucharest, Romania
    • The National Institute of Infectious Diseases Matei Bals
  • Cluj Napoca, Romania
    • Cluj Napoca Infectious disease Clinical Hospital
  • Cluj Napoca, Romania
    • Oncology Institute Ion Chiricuta Cluj Napoca
  • Iasi, Romania
    • Clinical Hospital Of Infectious Diseases Of Iasi
• Spain
  • Barcelona, Spain
    • Hospital Universitari Vall d´Hebron
  • Barcelona, Spain
    • Bellvitge Hospital
  • Cordoba, Spain
    • Hospital Universitario Reina Sofia
  • Madrid, Spain
    • Hospital Universitario 12 de Octubre
  • Madrid, Spain
    • Hospital Universitario Ramón y Cajal
  • Madrid, Spain
    • Hospital Universitario Gregorio Marañon
  • Sevilla, Spain
    • Hospital Universitario Virgen Macarena

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 50 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

• Sampling Method: Non-Probability Sample

Study Population

Patients aged 50 or older receiving oral or intervenous antibiotic treatment with Third or fourth generation cephalosporins, Fluoroquinolones, Penicillins +beta-lactamase inhibitors, Clindamycin, or Carbapenems during hospitalization.

Description

Inclusion Criteria:

1. Male or female hospitalized patient.
2. Aged ≥ 50 years old.

3. Initiation of intravenous or oral treatment with intended duration ≥5 days (≥1 day for clindamycin) with at least one of the following antibiotic classes, or treatment scheduled within the next 72 hours:

   • Third or fourth generation cephalosporins
   • Fluoroquinolones
   • Penicillins +beta-lactamase inhibitors
   • Clindamycin
   • Carbapenems
4. Written informed consent provided prior to inclusion.

Exclusion Criteria:

1. Ongoing antibiotic treatment with one of the above classes initiated >6 hours before inclusion into the study.
2. ICU admission at the time of inclusion or anticipated admission within 48h.
3. Suspected or diagnosed CDI, ongoing treatment for CDI, or diarrhoea at the time of inclusion.
4. Patient with stoma.
5. Subject has been included into this study previously.
6. Patient treated with probiotics to prevent CDI.
7. Patient with any social or logistical condition which in the opinion of the investigator may interfere with the conduct of the study, such as incapacity to well understand, not willing to collaborate, or cannot easily be contacted after discharge.
8. Subject is subject to legal protection.
9. Subject deprived of liberty by judicial or administrative decision.

Study Plan

How is the study designed?

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Clostridium difficile infection	28 days

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Clostridium difficile infection		90 days
Antibiotics associated diarrhea		90 days
Bacterial diversity	Change from baseline to day 6 of bacterial diversity and composition of the intestinal microbiome	6 days
Urine sulfate levels	Change from baseline to day 6 of 3-indoxyl sulfate levels in urine (corrected for the urine creatinine levels)	6 days

Collaborators and Investigators

• Sponsor: MJM Bonten
• Collaborators: Universiteit Antwerpen; Universitätsklinikum Köln; Da Volterra
• Investigators: Principal Investigator: Marc Bonten, MD, PhD, UMC Utrecht

Publications and helpful links

General Publications

• van Werkhoven CH, Ducher A, Berkell M, Mysara M, Lammens C, Torre-Cisneros J, Rodriguez-Bano J, Herghea D, Cornely OA, Biehl LM, Bernard L, Dominguez-Luzon MA, Maraki S, Barraud O, Nica M, Jazmati N, Sablier-Gallis F, de Gunzburg J, Mentre F, Malhotra-Kumar S, Bonten MJM, Vehreschild MJGT; ANTICIPATE Study Group. Incidence and predictive biomarkers of Clostridioides difficile infection in hospitalized patients receiving broad-spectrum antibiotics. Nat Commun. 2021 Apr 14;12(1):2240. doi: 10.1038/s41467-021-22269-y.
• Berkell M, Mysara M, Xavier BB, van Werkhoven CH, Monsieurs P, Lammens C, Ducher A, Vehreschild MJGT, Goossens H, de Gunzburg J, Bonten MJM, Malhotra-Kumar S; ANTICIPATE study group. Microbiota-based markers predictive of development of Clostridioides difficile infection. Nat Commun. 2021 Apr 14;12(1):2241. doi: 10.1038/s41467-021-22302-0.

Helpful Links

• COMBACTE consortium website: ANTICIPATE is WP7 of COMBACTE

Study record dates

Study Major Dates

• Study Start (Actual): September 27, 2016
• Primary Completion (Actual): January 23, 2018
• Study Completion (Actual): March 8, 2018

Study Registration Dates

• First Submitted: September 6, 2016
• First Submitted That Met QC Criteria: September 6, 2016
• First Posted (Estimate): September 12, 2016

Study Record Updates

• Last Update Posted (Actual): May 21, 2021
• Last Update Submitted That Met QC Criteria: May 18, 2021
• Last Verified: May 1, 2021

More Information

Terms related to this study

• Keywords: Clostridium difficile; microbiome; microbiota; antibiotics; Clostridium difficile infection; antibiotics associated diarrhea
• Additional Relevant MeSH Terms: Bacterial Infections; Bacterial Infections and Mycoses; Gram-Positive Bacterial Infections; Infections; Clostridium Infections
• Other Study ID Numbers: COMBACTE WP7

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO
• IPD Plan Description: 16S rRNA and shotgun metagenomic sequence data generated and analyzed in this study have been deposited in the NCBI Sequence Read Archive with the accession code PRJNA685914. Human reads were identified and removed prior to shotgun metagenomics data upload. Access to clinical data is restricted as the informed consent provided does not allow for use of clinical data outside the research institution. Data are available from the corresponding author upon reasonable requests.