ABSTRACT
Multidrug resistant organisms (MDROs) are bacteria that have become resistant to more than one antimicrobial
agent. Intestinal MDROs constitute a major threat to public health because they are increasingly difficult to treat
and result in increased costs, morbidity, and mortality when they spread outside of the gut. Clostridium difficile
shares many of the same characteristics as MDROs and along with MDROs has been labeled by the Centers
for Disease Control and Prevention as a national priority. No group suffers more from these intestinal MDROs
than nursing home residents. The perfect storm of a vulnerable group of frail older adults living in close
communities, with increased morbidity and mortality from bacterial infections, and corresponding high rates of
MDRO colonization emphasize the importance of the nursing home as a priority setting for studies to reduce
MRDO burden. The intestinal microbiome may be a key factor as it influences both the likelihood of de novo
colonization and whether colonization results in disease. In this proposal we will: 1) determine carriage rates of
key MDROs in nursing homes communities using novel rapid strain-specific technology (molecular inversion
probes); 2) assess the dissemination of pathogenic organisms; 3) determine in vivo/vitro how an aging
microbiome can induce intestinal inflammation, thus promoting MDRO colonization; and 4) determining the
extent to which both microbial dysbiosis and immunosenescence increases the risk of MDRO colonization,
infection, and worsening frailty. We hypothesize that environmental and clinical factors (e.g., medication)
characteristic of the NH settings contribute to and shape a dysbiotic microbiome that favors an increased risk of
MDRO colonization. We further hypothesize the extent of microbial dysbiosis will be the major contributor of
MDRO colonization, thus providing a novel target to combat pathogen prevalence within the NH environment.
Specifically, in Aim 1 we will develop and implement a cultivation-free, high-throughput, low-cost approach to
provide deep strain-level resolution of MDROs and accelerate epidemiological studies of infectious diseases.
Further we will derive a microbiome-based predictive tool, the NH-MDI, to assess individual risk of MDRO
colonization. Aim 2 will determine the mechanisms by which the microbiome can influence epithelial
homeostasis, thus providing a colonic microenvironment supportive of MDRO colonization. Aim 3 will include
analysis of stool and blood samples from a prospective nursing home cohort in order to determine the relative
contribution of aging microbiome dysbiosis to markers of immunosenescence for increased risk of MDRO
colonization as well as risk of worsening frailty. Further, we will determine the extent that dysbiosis and
immunosenescence correlates with risk of future infection over 18 months of follow-up. Defining these crucial
parameters will provide the basis for development of novel microbiome therapeutics aimed at the prevention of
nursing home infections and promoting healthy aging. In doing so, we will further develop novel approaches to
identify infectious organisms that will be superior to current diagnostic methods.
