NCCR AntiResist:: New Approaches to Combat Antibiotic-resistant Bacteria

Study Overview
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Brief Summary
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This is an explorative, mono-center study including prospectively collected patient samples from the University Hospital of Basel. It is to investigate antimicrobial resistance (AMR) including three clinical manifestations of infectious diseases: urinary tract infection, pneumonia and deep-seated infections. The focus is on four bacteria (E. coli, Klebsiella species, S. aureus, P. aeruginosa) that are part of the high priority list of World Health Organization (WHO). Residual patient samples are analysed for proteomic, metabolomic and transcriptomic analysis, immunocytochemical or fluorescence in-situ hybridisation (FISH) analysis, flow cytometry analysis (FACS) and immunophenotyping and exploration of bacterial properties.

Detailed Description
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The National Center of Competence in Research (NCCR) AntiResist aims at utilizing patient samples in order to investigate the physiology of bacterial pathogens in human patients and establishing a unique multidisciplinary network of clinicians, biologists, engineers, chemists, computational scientists and drug developers. The goal of this project is to elucidate the physiological properties of bacterial pathogens in infected human patients in order to provide new ways of combatting superbugs. These clinical data will be used to guide and benchmark development of patient-mimicking and in-vitro models, accelerate the search for novel bacterial targets, antibacterial compounds and non-conventional strategies. In detail, the focus will be on three clinical manifestations of infectious diseases caused by four critical bacterial pathogens belonging to WHO priority pathogens list: E. coli, Klebsiella species, S. aureus and P. aeruginosa : A) Urinary tract infection B) Pneumonia C) Deep-seated infections D) Controls for A), B) and C) E) Clinical controls for A), B) and C) without obtained samples F) Analysis whether the application of Art. 34 HFV (Weiterverwendung biologischen Materials und/oder gesundheitsbezogener Personendaten für die Forschung bei fehlender Einwilligung und Information) can avoid a bias.

Official Title
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NCCR AntiResist: Mono-center Study to Identify New Approaches to Combat Antibiotic-resistant Bacteria.

Conditions
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Antimicrobial Resistance (AMR)

Intervention / Treatment
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* Other: analysis of antimicrobial resistance


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients with confirmed (i) urinary tract infection, (ii) pneumonia (including patients after lung transplantation, cystic fibrosis) or (iii) deep-seated infection with focus pathogen: E. coli Klebsiella species S. aureus P. aeruginosa Controls: no detectable bacteria in routine microbiology lab and no other infection site at inclusion of the sample and follow up for 10 days, signed general consent Clinical controls without obtained samples, but with confirmed (i) urinary tract infection, (ii) pneumonia (including patients after lung transplantation, cystic fibrosis) or (iii) deep-seated infection with focus pathogen: E. coli Klebsiella species S. aureus P. aeruginosa Exclusion Criteria: Patients who have refused research and reuse of their data/samples (e.g. general consent) or any other decline (e.g. Patientenverfügung). other than one of the focus bacteria in routine microbiology lab Age: <18 years Controls without signed general consent

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| A) Urinary tract infection<br>Processing of residual urine for proteomic, metabolomic and transcriptomic analysis, immunocytochemical or fluorescence in-situ hybridisation (FISH) analysis, flow cytometry analysis (FACS), immunophenotyping. If positive for target bacteria: sample stored at biobank. If previous antibiotic treatment: plasma sample storage. Exploration of bacterial properties (Highly sensitive mass spectrometry, whole genome sequencing), expression of virulence factors, genomic alterations of bacterial species, metabolism, surface molecule expression, gene expression levels, cytokine levels, immune cell biology, antibiotic concentration (chromatography/mass spectrometry). Demographical, clinical, microbiological, laboratory, epidemiological and hospital-associated data will be analysed. 500 samples per target bacteria (S. aureus, P. aeruginosa, E. coli, Klebsiella species) included. First, a pilot study from randomly selected patients within each bacterial species group (n=50, each) is done. | Other: analysis of antimicrobial resistance<br>* In samples from patients infected with one of the focus pathogens (E. coli, Klebsiella species, S. aureus, P. aeruginosa) will be: (i) isolated and pathogenic bacteria characterized; (ii) pathogen in-situ properties at single-cell and bulk average determined; (iii) human metabolites, proteins and cells determined (iv) antibiotic concentration determined (v) bacterial growth monitored Deducted from the data will be: relevant human components and pathogen properties that are common to most patients with similar indication underlying regulatory networks and triggers in pathogen cells and human tissues. Clinical outcomes (survival/mortality) and treatment response (response or failure) will be correlated to the in vitro retrieved host and bacterial data.<br>|
| B) Pneumonia<br>Processing of residual samples (tracheal secretion, bronchioalveolar lavage (BAL)) for proteomic, metabolomic, transcriptomic and cytological analysis. If positive for target bacteria: sample stored at biobank. If previous antibiotic treatment: plasma sample storage. Exploration of bacterial properties. Demographical, clinical, microbiological, laboratory, epidemiological and hospital-associated data will be analysed. 500 samples per target bacteria (S. aureus, P. aeruginosa, E. coli, Klebsiella species) included. | Other: analysis of antimicrobial resistance<br>* In samples from patients infected with one of the focus pathogens (E. coli, Klebsiella species, S. aureus, P. aeruginosa) will be: (i) isolated and pathogenic bacteria characterized; (ii) pathogen in-situ properties at single-cell and bulk average determined; (iii) human metabolites, proteins and cells determined (iv) antibiotic concentration determined (v) bacterial growth monitored Deducted from the data will be: relevant human components and pathogen properties that are common to most patients with similar indication underlying regulatory networks and triggers in pathogen cells and human tissues. Clinical outcomes (survival/mortality) and treatment response (response or failure) will be correlated to the in vitro retrieved host and bacterial data.<br>|
| C) Deep-seated infections<br>Processing of intraoperative material residual samples for proteomic, metabolomic, transcriptomic and cytological analysis. If positive for target bacteria: sample stored at biobank. Exploration of bacterial properties. Demographical, clinical, microbiological, laboratory, epidemiological and hospital-associated data will be analysed. 500 samples per target bacteria (S. aureus, P. aeruginosa, E. coli, Klebsiella species) included. | Other: analysis of antimicrobial resistance<br>* In samples from patients infected with one of the focus pathogens (E. coli, Klebsiella species, S. aureus, P. aeruginosa) will be: (i) isolated and pathogenic bacteria characterized; (ii) pathogen in-situ properties at single-cell and bulk average determined; (iii) human metabolites, proteins and cells determined (iv) antibiotic concentration determined (v) bacterial growth monitored Deducted from the data will be: relevant human components and pathogen properties that are common to most patients with similar indication underlying regulatory networks and triggers in pathogen cells and human tissues. Clinical outcomes (survival/mortality) and treatment response (response or failure) will be correlated to the in vitro retrieved host and bacterial data.<br>|
| D) Controls for A), B) and C)<br>Control samples result from patients with a suspected infection (infection sites A), B) or C), in which no microbiological confirmed infection has been diagnosed. Storage at biobank | Other: analysis of antimicrobial resistance<br>* In samples from patients infected with one of the focus pathogens (E. coli, Klebsiella species, S. aureus, P. aeruginosa) will be: (i) isolated and pathogenic bacteria characterized; (ii) pathogen in-situ properties at single-cell and bulk average determined; (iii) human metabolites, proteins and cells determined (iv) antibiotic concentration determined (v) bacterial growth monitored Deducted from the data will be: relevant human components and pathogen properties that are common to most patients with similar indication underlying regulatory networks and triggers in pathogen cells and human tissues. Clinical outcomes (survival/mortality) and treatment response (response or failure) will be correlated to the in vitro retrieved host and bacterial data.<br>|
| E) Clinical controls for A), B) and C) without obtained samples<br>For clinical controls, clinical characteristics of patients with detection of target pathogens in their routine samples (but which could not be included for sample analysis in this study) will be assessed. | Other: analysis of antimicrobial resistance<br>* In samples from patients infected with one of the focus pathogens (E. coli, Klebsiella species, S. aureus, P. aeruginosa) will be: (i) isolated and pathogenic bacteria characterized; (ii) pathogen in-situ properties at single-cell and bulk average determined; (iii) human metabolites, proteins and cells determined (iv) antibiotic concentration determined (v) bacterial growth monitored Deducted from the data will be: relevant human components and pathogen properties that are common to most patients with similar indication underlying regulatory networks and triggers in pathogen cells and human tissues. Clinical outcomes (survival/mortality) and treatment response (response or failure) will be correlated to the in vitro retrieved host and bacterial data.<br>|
| F) Cohort with analysis whether the application of Article (Art) 34 HFV can avoid a bias<br>Since part of the data and samples in this study are collected with the representative consent of the ethics committees, it is investigated whether the application of Art. 34 HFV prevents selection bias with respect to the study population. For this purpose, differences between the actual study population using Art. 34 HFV and the study population with provided research consent will be descriptively investigated in terms of the prevalence of multi-resistant germs and other available population characteristics. | Other: analysis of antimicrobial resistance<br>* In samples from patients infected with one of the focus pathogens (E. coli, Klebsiella species, S. aureus, P. aeruginosa) will be: (i) isolated and pathogenic bacteria characterized; (ii) pathogen in-situ properties at single-cell and bulk average determined; (iii) human metabolites, proteins and cells determined (iv) antibiotic concentration determined (v) bacterial growth monitored Deducted from the data will be: relevant human components and pathogen properties that are common to most patients with similar indication underlying regulatory networks and triggers in pathogen cells and human tissues. Clinical outcomes (survival/mortality) and treatment response (response or failure) will be correlated to the in vitro retrieved host and bacterial data.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Clinical outcome: survival rate | Survival rate (correlated to the in vitro retrieved host and bacterial data. In vitro retrieved host and bacterial data include: Proteomics, Metabolomics, FISH, Histology, PCR/Microbial genome sequencing, Microbial transcriptome, Antibiotic concentration, Timelapse studies, phenotypic characterisations, molecular typing, innate immune response characterization, Antibiotic tolerance testing, Microfluidic systems, 3-D models, Transcriptomics, Flow cytometry (FACS)) | one time assessment at baseline | 
| Clinical outcome: mortality rate | Mortality rate (correlated to the in vitro retrieved host and bacterial data. In vitro retrieved host and bacterial data include: Proteomics, Metabolomics, FISH, Histology, PCR/Microbial genome sequencing, Microbial transcriptome, Antibiotic concentration, Timelapse studies, phenotypic characterisations, molecular typing, innate immune response characterization, Antibiotic tolerance testing, Microfluidic systems, 3-D models, Transcriptomics, Flow cytometry (FACS)) | one time assessment at baseline | 
| Treatment response (binary: yes/ no) | Treatment response (correlated to the in vitro retrieved host and bacterial data. In vitro retrieved host and bacterial data include: Proteomics, Metabolomics, FISH, Histology, PCR/Microbial genome sequencing, Microbial transcriptome, Antibiotic concentration, Timelapse studies, phenotypic characterisations, molecular typing, innate immune response characterization, Antibiotic tolerance testing, Microfluidic systems, 3-D models, Transcriptomics, Flow cytometry (FACS)) | one time assessment at baseline | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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National Center of Competence in Research (NCCR), Urinary tract infection (UTI), Pneumonia, Deep-seated infections, E. coli, Klebsiella species, S. aureus, P. aeruginosa, bacterial properties, Community-acquired pneumonia (CAP), Hospital-acquired pneumonia (HAP), Ventilator-associated pneumonia (VAP), cystic fibrosis (CF)