Impact of Prescription Quality, Infection Control and Antimicrobial Stewardship on Gut Microbiota Domination by Healthcare-Associated Pathogens (PILGRIM)

Extended-spectrum beta-lactamase producing Enterobacteriaceae (EPE), vancomycin-resistant enterococci (VRE) and Clostridium difficile have become a major threat to hospitalised patients worldwide. We hypothesize that receiving inappropriate antibacterial treatment places patients at high risk of intestinal domination and subsequent infection by these bacteria. Further analyses will address cost-effectiveness of specific interventions, behavioural analyses of the decision process leading to inappropriate antibacterial treatment, and the rate of undetected colonization with EPE/VRE/C. difficile on admission.

Study Overview

• Status: Unknown
• Conditions: Patients at High Risk of Antibacterial Treatment Upon Admission

Detailed Description

The prevalence of antimicrobial resistant pathogens has dramatically increased among hospitalised patients worldwide. While various management strategies have effectively reduced the burden caused by methicillin-resistant Staphylococcus aureus, resistant pathogens with a preference towards intestinal colonization are currently on the rise. E.g., vancomycin-resistant enterococci (VRE) and extended-spectrum beta-lactamase producing Enterobacteriaceae (EPE) now constitute a significant threat to hospitalised patients worldwide, as infections due to these organisms require prolonged treatments and result in inferior outcomes. Similarly, the burden of disease caused by Clostridium difficile infection (CDI), the main cause of healthcare-associated infectious diarrhoea, has increased driven by the emergence of hypervirulent strains such as ribotypes 027 and 078. Molecular studies have demonstrated that increased population-wide exposure to broad-spectrum antibacterials is a crucial step in the initiation of outbreaks by selection and expansion of resistant C. difficile.

This is a comprehensive, multinational, multi-centre clinical study aiming to assess the impact of inappropriate antibacterial prescription on intestinal domination by EPE or VRE or infection with C. difficile. To achieve this goal, the study will closely follow the progression from first acquisition of drug-resistant organisms to infection with these bacteria at an individual patient level.

In this study, we will establish the sequence and factors involved in acquisition, colonization, selective pressure, bacterial overgrowth/domination/ and infection for EPE, VRE and C. difficile. We hypothesize that IC (Infection Control; prevention of pathogen acquisition) and AMS (Antimicrobial Stewardship; prevention of clonal expansion) measures leading to a higher share of appropriate anti-infective use are effective strategies to prevent this development. The study programme will allow an accurate estimation of the preventable share of healthcare-acquired colonization and infection by VRE, EPE, and C. difficile.

No direct interventions will be performed with study patients. Instead, study centres will assess quality indicators for implementation of IC and AMS measures by active observation and aggregation of data. Patients fulfilling all inclusion- and no exclusion criteria will be asked for their consent to be recruited prospectively into a cohort study. During the observational phase, participants will be monitored for receipt of antibacterial treatment and regular stool samples will be obtained and stored. An interdisciplinary, international AMS Board will comprehensively assess antibiotic treatment via review by a panel of experts. After the observation is completed, stool samples will be batch-tested for intestinal domination by the target pathogens of this study. Statistical analyses will be performed to investigate an association between inappropriate antibiotic use as opposed to appropriate or no antibiotic use and intestinal domination. If domination is detected, further analyses for phenotype, quantity, resistance, and molecular biology will be performed. Finally, the baseline sample will be tested for presence of the dominant species to understand the source of the pathogen, i.e. nosocomial versus outpatient acquisition.

• Study Type: Observational
• Enrollment (Anticipated): 1500

Contacts and Locations

• Study Contact: Name: Jörg Janne Vehreschild, MD; Phone Number: 88794 +49227478; Email: joerg.vehreschild@uk-koeln.de
• Study Contact Backup: Name: Annika Löhnert, MD; Email: annika.loehnert@uk-koeln.de

Study Locations

• Germany
  • NRW
    • Cologne, NRW, Germany, 50931
      • Recruiting
      • University Hospital of Cologne
      • Contact: Jörg Janne Vehreschild, MD; Email: joerg.vehreschild@uk-koeln.de

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

• Sampling Method: Non-Probability Sample

Study Population

Hospitalized patients at high risk of receiving antibiotic treatment during their hospital stay will be screened for study eligibility.

Description

Inclusion Criteria:

1. Age ≥ 18 years
2. Planned treatment or high likelihood of any systemic antibacterial treatment except trimethoprim/sulfamethoxazole within the next 10 days for a duration of ≥ 5 days
3. Patients able to provide a stool sample before or within 4 hours of receiving first antibiotic dosage
4. Written informed consent provided prior to inclusion

Exclusion Criteria:

1. Patients who have received courses of systemic antibacterials for 7 days or more within the past two months
2. Patients having received any antibacterial compound other than trimethoprim/sulfamethoxazole within 14 days prior to study enrolment except first antibiotic dosage within 4 hours prior enrolment
3. Patients with diarrhea at enrolment (≥3 unformed bowel movements within 24h)
4. Patients with a stoma (jejunostomy, ileostomy, or colostomy) at time of inclusion
5. Patients on enteral (tube fed or PEG) or parenteral nutrition
6. 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
7. Patients exclusively treated as outpatients without prior hospital admission
8. Previous participation in this study

Study Plan

How is the study designed?

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Impact of inappropriate antibacterial prescription on intestinal microbiota domination by healthcare associated pathogens	The differential impact of inappropriate antibacterial prescription compared to adequate or no antibacterial prescription on intestinal microbiota domination by EPE or VRE or infection with C. difficile measured by analysing stool samples.	up to 6 - 36 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Time-point of Intestinal Colonization	Determination of the rate of in-hospital vs. pre-admission intestinal colonization with EPE, VRE, and/or C. difficile measured by analysing stool samples.	Baseline and up to 6 - 36 weeks
Time-point of Intestinal Domination	Determination of the rate of in-hospital vs. pre-admission intestinal domination with EPE, VRE, and/or C. difficile measured by analysing stool samples.	Baseline and up to 6 - 36 weeks
Inter-rater reliability of AMS specialists	Determination of the inter-rater reliability of interdisciplinary AMS specialists rating antibacterial prescription appropriateness.	After complete documentation of each patient case (follow-up for 6-36 weeks) followed by completed ratings of AMS specialists
Rationale for antibacterial prescription habits assessed by performing qualitative interviews with prescribing physicians	Identification of behavioral determinants and knowledge gaps leading to inappropriate antibacterial prescriptions by interviewing approximately 50 prescribing physicians.	After complete documentation of patient case (follow-up for 6-36 weeks) through study completion
Correlation of prescription and AMS implementation	Assessment of the correlation of appropriate antibacterial prescription with quality indicators of AMS implementation	Baseline, 12 months, 24 months
Identification of risk factors responsible for disrupting the intestinal microbiota	Identification of risk factors for colonization, intestinal domination, and infection by EPE, VRE and C. difficile, including comorbidities and drugs known to disrupt the intestinal microbiota, and high-risk bacterial clones prone to dominate the microbiota due to high fitness. Assessment by analysing stool samples and documented data.	Baseline and weekly up to 6 - 36 weeks of follow-up

Collaborators and Investigators

• Sponsor: University Hospital of Cologne
• Collaborators: Karolinska Institutet; University Hospital of North Norway; Goethe University; McGill University Health Centre/Research Institute of the McGill University Health Centre; Rabin Medical Center; Helse Stavanger HF; Haukeland University Hospital; University Hospital, Akershus; University of Latvia
• Investigators: Principal Investigator: Jörg Janne Vehreschild, MD, University Hospital Cologne

Study record dates

Study Major Dates

• Study Start (Actual): January 1, 2019
• Primary Completion (Anticipated): July 31, 2021
• Study Completion (Anticipated): July 31, 2022

Study Registration Dates

• First Submitted: November 16, 2018
• First Submitted That Met QC Criteria: December 4, 2018
• First Posted (Actual): December 5, 2018

Study Record Updates

• Last Update Posted (Actual): August 3, 2020
• Last Update Submitted That Met QC Criteria: July 30, 2020
• Last Verified: July 1, 2020

More Information

Terms related to this study

• Keywords: Microbiome; Clostridium difficile; Antimicrobial resistance; Infection Control; Nosocomial infection; Antimicrobial Stewardship; Extended-Spectrum β-Lactamase producing Enterobacteriaceae; Vancomycin-resistant enterococci
• Additional Relevant MeSH Terms: Infections
• Other Study ID Numbers: PILGRIM

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No