ISAC Award Program Application Concept

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Metagenomic sequencing for improved diagnosis of catheter-associated urinary tract infection
Chelsie Armbruster   (Buffalo, NY)
Diagnosis and effective treatment of catheter-associated urinary tract infection (CAUTI) is hindered by numerous challenges, especially in patient populations with long-term indwelling catheters. In a recent prospective longitudinal study, we made two critical observations: 1) patients with long-term catheters exhibit persistent asymptomatic colonization by pathogenic bacteria, and 2) the bacteria identified as the causative agents of symptomatic CAUTIs had been present asymptomatically for several weeks prior to diagnosis. Thus, in direct challenge to the traditional approach for CAUTI diagnosis and treatment, new acquisition of pathogenic bacteria was not the cause of infection symptoms. We hypothesize that sign and symptom onset in this patient population instead corresponds to one of the following: i) new acquisition of non-traditional fastidious bacteria undetected by standard urine culture methods; ii) new acquisition of a non-bacterial pathogen, such as a parasite or virus; iii) dysbiosis of the microbial community; or iv) a change in the functional capacity of the microbial community that allows a colonizing microbe to shift to a pathogenic lifestyle. Our saved longitudinal urine specimens provide the ideal framework for applying shotgun metagenomics sequencing to address this hypothesis. The majority of urine microbiome studies have focused on bacteria, and catheter urine specimens pose unique challenges for the feasibility and economics of metagenomics sequencing. We therefore propose to develop best practices for extracting all microbial DNA (bacteria, fungi, parasites, viruses) from complex catheter urine specimens, building reproducible analysis pipelines to generate a quantitative analysis of the number, identity, and proportion of all microbes in the sample, and aligning composition and functional capacity over time with sign and symptom onset for diagnosed and treated CAUTIs. Identifying previously-unrecognized CAUTI pathogens and pathogenicity elements that correlate with sign and symptom onset, especially for eukaryotic microbes and viruses, is a high-risk project with high potential to disrupt current paradigms of UTI/CAUTI diagnosis to ultimately improve monitoring and treatment of infection in a vulnerable and underserved patient population. The methods that we propose to develop will also facilitate exploration of the full microbial contribution to other common urologic conditions, which have predominantly focused on bacterial composition.
Data for this report has not yet been released.

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