Clinical trial NCT03765528: Impact of Prescription Quality, Infection Control and Antimicrobial Stewardship on Gut Microbiota Domination by Healthcare-Associated Pathogens
Official title: Impact of Prescription Quality, Infection Control and Antimicrobial Stewardship on Gut Microbiota Domination by Healthcare-Associated Pathogens
Study type: OBSERVATIONAL
Overall status: UNKNOWN
Conditions: Patients at High Risk of Antibacterial Treatment Upon Admission
Keywords: Clostridium difficile
Extended-Spectrum β-Lactamase producing Enterobacteriaceae
Vancomycin-resistant enterococci
Antimicrobial resistance
Microbiome
Nosocomial infection
Antimicrobial Stewardship
Infection Control
Lead sponsor: University Hospital of Cologne
Sponsor class: OTHER
Collaborators: name: University Hospital of North Norway
name: Karolinska Institutet
name: Rabin Medical Center
name: University of Latvia
name: McGill University Health Centre/Research Institute of the McGill University Health Centre
name: Haukeland University Hospital
name: University Hospital, Akershus
name: Helse Stavanger HF
name: Goethe University
First posted: 2018-12-05
Enrollment: 1500
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Observational model: COHORT
Time perspective: PROSPECTIVE
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.

Brief summary: 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.

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.

Eligibility criteria: 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

Primary outcomes:
measure: Impact of inappropriate antibacterial prescription on intestinal microbiota domination by healthcare associated pathogens
timeFrame: up to 6 - 36 weeks
Secondary outcomes:
measure: Time-point of Intestinal Colonization
timeFrame: Baseline and up to 6 - 36 weeks
measure: Time-point of Intestinal Domination
timeFrame: Baseline and up to 6 - 36 weeks
measure: Inter-rater reliability of AMS specialists
timeFrame: After complete documentation of each patient case (follow-up for 6-36 weeks) followed by completed ratings of AMS specialists
measure: Rationale for antibacterial prescription habits assessed by performing qualitative interviews with prescribing physicians
timeFrame: After complete documentation of patient case (follow-up for 6-36 weeks) through study completion
measure: Correlation of prescription and AMS implementation
timeFrame: Baseline, 12 months, 24 months
measure: Identification of risk factors responsible for disrupting the intestinal microbiota
timeFrame: Baseline and weekly up to 6 - 36 weeks of follow-up
Other outcomes:
Locations:
city: Cologne
country: Germany
facility: University Hospital of Cologne
state: NRW
Study officials:
affiliation: University Hospital Cologne
name: Jörg Janne Vehreschild, MD
role: PRINCIPAL_INVESTIGATOR
References: