Jennie Kwon, D.O.
Project Summary:
Urinary tract infections (UTIs) affect 150 million people a year worldwide and account for $3.5 billion dollars in health care and societal costs in the U.S. alone. UTIs of particular concern are those caused by multidrug-resistant organisms (MDROs), which are bacteria resistant to most available antibiotics and often referred to as “superbugs.” Antibiotic resistance is a critical public health issue, and it is estimated that MDRO infections will cause more deaths than cancer by 2050. Furthermore, it is estimated that by 2050, 10 million lives per year and a cumulative US$100 trillion of economic output are at risk due to MDROs.
UTIs are the most common type of MDRO infections, and up to 30% of patients with a first MDRO UTI experience a recurrence. UTIs are the most common type of infection in the elderly, and the elderly are at high risk for MDRO infections. The human gastrointestinal tract is a common source of MDRO UTIs, as the gut bacteria contaminate the outside of the urethra, then travel to the bladder to cause a UTI. In order to create methods to prevent MDRO infections and recurrence of infections, we propose a study to understand the fecal microbiome in patients with MDRO UTIs.
Our study has two main goals. The first is to understand changes in the fecal microbiome of patients who develop MDRO UTI. There are no studies of the fecal microbiome in patients with MDRO UTI, therefore this is a necessary step. We hypothesize that at the time of the acute infection, the MDRO causing the UTI will be present at a high concentration in the fecal microbiota. After appropriate treatment, we hypothesize that the MDRO concentration will decrease in the gut (as compared to the pre-treatment time-point) but will not be completely eliminated. Our second goal is to identify bacterial communities associated with recurrent MDRO UTIs. We hypothesize there are microbial communities in the gut associated with an increased risk for recurrent UTI, and identification of these communities can be used to predict patients who will develop recurrent UTI. Once we understand the types of microbial communities that present in the fecal microbiota, we can then develop interventions to predict recurrent MDRO infections and future methods to prevent infection.
In this study, we will recruit patients with MDRO UTIs and utilize culture-based and metagenomic techniques to characterize the GI microbiome. Culture-based methods allow us to isolate the MDRO causing the UTI. Metagenomic techniques directly analyze bacterial DNA extracted from specimens, enabling a culture-independent understanding of the different type of microbial communities within a given environment. We will recruit patients with MDRO UTIs and obtain urine and stool specimens at multiple time points from the time of initial infection. At each time point, we will collect detailed information on symptoms, medical history, medication exposures, and dietary intake. We have already recruited 12 patients for this study, four of whom had recurrent UTIs, and have collected 97 urine and 70 stool specimens from these subjects. Funding from The Longer Life Foundation (LLF) would allow continued processing of specimens via microbiologic and metagenomic methods.
Final Report
We recruited 14 patients with MDRO UTI (seven with recurrences, seven without). Our WGS and culture results determined that clonal MDROs including uropathogenic Escherichia coli, Proteus mirabilis, and Klebsiella pneumoniae isolates can be found in the intestinal and urinary tracts of patients affected by recurrent and non-recurrent UTIs. Clonal tracking of isolates in consecutively collected urine and gut specimens indicated repeated transmission of uropathogens between the urinary tract and their intestinal reservoir. Our results further implicate three independent routes of recurrence of UTIs: (i) following an intestinal bloom of uropathogenic bacteria and subsequent bladder colonization, (ii) reinfection of the urinary tract from an external source, and (iii) bacterial persistence within the urinary tract.
Taken together, our observation of clonal persistence following UTIs and uropathogen transmission between the intestinal and urinary tracts warrants further investigations into the connection between the intestinal microbiome and recurrent UTIs.
