Dynamics of Colonization and Infection by Multidrug-resistant Pathogens in Immunocompromised and Critically Ill Patients (DYNAMITE)

ABSTRACT - OVERALL
Dynamics of Colonization and Infection by Multidrug-Resistant Pathogens in Immunocompromised
and Critically Ill Patients (DYNAMITE) Program.
Antimicrobial resistance (AMR) in community and hospital-associated pathogens has been named one of the
most pressing public health priorities by the United Nations. Among the most relevant multidrug-resistant
(MDR) bacteria, vancomycin-resistant enterococci (VRE), extended spectrum β-lactamase
producing/carbapenem-resistant Enterobacteriaceae (ESBL-E/CRE) and Clostridiodes difficile are
considered high priority inasmuch as these organisms commonly infect severely ill and immunocompromised
patients, and there is a paucity of therapeutic options to treat infections caused by these bacteria. For each of
these key pathogens, the intestines are the site of initial colonization and, under the influence of broad-
spectrum antimicrobial therapies, these organisms can “dominate” the gastrointestinal tract increasing the risk
of clinical disease. Importantly, it is becoming progressively clear that colonization of the intestines by either
VRE, ESBL-E/CRE, or C. difficile is markedly associated with subsequent colonization by other members of
this group, but whether pathogen-to-pathogen signaling plays a role is not known. Further, data generated from
microbiome-based studies to date has not allowed for clinically impactful interventions due to the imprecise
identification of high-risk patients and it is currently unclear why only a subset of patients, under apparently
similar conditions, develop colonization/disease. Our overarching hypothesis is that patient susceptibility to
gut-derived nosocomial colonization and subsequent infection is critically dependent on functional microbiota-
pathogen interactions that can be detected via a holistic combination of pathogen, host, and commensal
microbiota analyses. The DYNAMITE program (Dynamics of Colonization and Infection by Multidrug-Resistant
Pathogens in Immunocompromised and Critically Ill Patients) seeks to fill these important gaps in knowledge.
Indeed, we have identified keystone microbiota features that are broadly protective against gut-derived
pathogens via previously unappreciated antimicrobial mechanisms suggesting that lack of such organisms may
be a critical factor in determining pathogen colonization and infection. The aims of the program are, i) dissect
the main microbial, clinical and antimicrobial resistance determinants that impact colonization and infection by
VRE, ESBL-E/CRE and C. difficile, ii) evaluate the role of the commensal microbiota in VRE, ESBL-E/CRE
and C. difficile colonization, and iii) define the functional aspects of keystone microbiota and mechanisms of
protection against colonization/infection. Our strong history of multi-institutional collaboration on AMR and
microbiome science with centralized state-of-the art facilities, administrative resources, and access to two
major cohorts of critically ill and immunocompromised patients in the Texas Medical Center, place our team in
a unique and ideal position to achieve the goals. We expect that the findings of our high impact,
complementary projects will provide critical platforms for the development of novel diagnostic, preventive, and
therapeutic approaches to combat gut-derived AMR organisms affecting critically ill individuals.

Grant Number: 5P01AI152999-05
NIH Institute/Center: NIH
Principal Investigator: Cesar Arias