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Conference object . 2024
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The COMBINE Preclinical Bacterial Strain Repository (PBSR)

A new resource for preclinical lung infection models to assess antibiotic efficacy
Authors: Kerscher, Bernhard; Azzazuria, Rakel; Vingsbo Lundberg, Carina; Hansen, Jon Ulf; Hoover, Jennifer L.; Sordello, Sylvie; Gribbon, Philip; +3 Authors

The COMBINE Preclinical Bacterial Strain Repository (PBSR)

Abstract

Background The rise in antimicrobial resistance (AMR) and increase in treatmentrefractory AMR infections, generates an urgent need to accelerate the discovery and development of novel anti-infectives. Preclinical animal models play a crucial role in assessing the efficacy of novel drugs, informing human dosing regimens and progressing drug candidates into the clinic. The Innovative Medicines Initiative-funded “Collaboration for prevention and treatment of MDR bacterial infections” COMBINE consortium is establishing a validated and globally harmonized murine lung infection model to increase comparability and reproducibility of preclinical efficacy studies and more reliably translate results from animals to humans. Virulence screening To date, we have screened 33 bacterial isolates for virulence in our proposed standard lung infection model and 5 isolates each of Klebsiella pneumoniae and Pseudomonas aeruginosa were assessed for interlaboratory reproducibility of virulence. Strains meeting our COMBINE criteria, i.e. at least a ten-fold increase in lung bacterial burden between 2 hours post infection and the experimental endpoint (26 hours post infection or the humane endpoint) and an endpoint not earlier than 12 hours post infection, were included as potential reference strains. Additional isolate characterization and in vivo validation studies are currently ongoing and data will be made available as part of the PBSR. Development of the COMBINE standard pneumonia model We recently reviewed the literature on commonly used antibiotics efficacy models [1] and developed a consensus mouse lung infection model based on our findings and a public stakeholder workshop with experts from industry, academia and medicines regulation [2]. Launch of the PBSR with virulent candidate strains Here, we report the launch of our COMBINE Preclinical Bacterial Strain Repository (PBSR) which will provide Gram-negative bacterial isolates to interested investigators. Strain information is being made available via the PEI website. Strains have been deposited to the German Collection of Microorganisms and Cell Cultures (DSMZ) for maintenance and distribution. Reference strain selection workflow COMBINE acquired bacterial isolates based on shareability, clinical relevance and molecular characteristics, which are being further characterised, assessed for in vivo virulence and validated in dosing studies with reference treatments. Chosen to test based on Shareability Antibiotic susceptibiliyt testing profile Contemporary (if possible) Characterisation (if available) Candidate strains selected by Virulence Standard protocol criteria Mortality/pathogenicity Expected +/- efficacy response for control compounds Refernece strains chosed baesd on Inter-lab reproducibility PK/PD characterisation Outlook Protocol and strain validation with antibiotics dose-ranging studies. Model validation in ring studies. Publication of strain and model characterization data. The PBSR in combination with the COMBINE standard protocol and our validation data will provide an important resource to investigators to facilitate model validation and enhance the comparability of preclinical antibiotics efficacy data. COMBINE Pneumonia Model resources COMBINE preclinical repository with bacterial strains found to be reproducibly virulent and fulfilling performance criteria in the COMBINE standardised pneumonia mouse model. Data from the COMBINE Multicenter Study to Standardize a Mouse Pneumonia Model with Pseudomonas aeruginosa and Klebsiella pneumoniae for Antibiotic Development Arrazuria R, Kerscher B, Huber KE, Hoover JL, Lundberg CV, Hansen JU, Sordello S, Renard S, Aranzana-Climent V, Hughes D, Gribbon P, Friberg LE, Bekeredjian-Ding I (2022): Expert workshop summary: Advancing toward a standardized murine model to evaluate treatments for antimicrobial resistance lung infections.Front Microbiol 13: 988725. Arrazuria R, Kerscher B, Huber KE, et al. Variability of murine bacterial pneumonia models used to evaluate antimicrobial agents. Frontiers in Microbiology. 2022;13:988728. 

Keywords

Klebsiella pneumoniae, Bacteria, Virulence, Antibiotic resistance, Antibiotics, Bacteria/chemistry, COMBINE pneumonia model, Pseudomonas aeruginosa, PK/PD, AMR, preclinical research, Pneumonia, In vivo assay

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selected citations
These citations are derived from selected sources.
This is an alternative to the "Influence" indicator, which also reflects the overall/total impact of an article in the research community at large, based on the underlying citation network (diachronically).
BIP!Citations provided by BIP!
popularity
This indicator reflects the "current" impact/attention (the "hype") of an article in the research community at large, based on the underlying citation network.
BIP!Popularity provided by BIP!
influence
This indicator reflects the overall/total impact of an article in the research community at large, based on the underlying citation network (diachronically).
BIP!Influence provided by BIP!
impulse
This indicator reflects the initial momentum of an article directly after its publication, based on the underlying citation network.
BIP!Impulse provided by BIP!
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