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Detecting Lower Intestinal Microbiome Disruption and Multidrug Resistant Organisms

Background
Antibiotic resistance causes over 2 million infections and 23,000 deaths annually in the United States alone and is a global public health challenge that has reached critical levels in healthcare settings, and the evolution of multidrug-resistant organisms (MDROs) threaten to move the care of hospitalized patients into a pre-antibiotic era. These MDROs include organisms such as vancomycin-resistant enterococcus (VRE), carbapenem-resistant Enterobacteriaceae (CRE), extended-spectrum beta-lactam resistant Enterobacteriaceae (ESBLs), and Clostridium difficile, all of which primarily colonize patients in the lower intestine where they undergo clonal expansion and often dominate the microbiome.  Prerequisite for colonization by these intestinal MDROs are disruption and shift in diversity of the lower intestinal microbiome that usually result from exposure to antibiotics, but may be contributed to by other medications, dietary changes, and diarrhea from viral and non-infectious causes.  Following colonization, dominance of the lower intestinal microbiome by a particular MDRO (as defined by constituting >30% of the microbiome) is a risk factor for infection. Moreover, intestinal MDRO dominance, over and above low-level colonization, is associated with increased skin and environmental contamination, and risk of transmission.
Investigations are underway to identify critical taxonomic and functional components of the intestinal microbiome that, when absent, confer risk for colonization or infection with MDROs. Meanwhile, current infection control and public health recommendations often include active surveillance testing to detect and contain transmission from patients who are asymptomatically colonized with the aforementioned MDROs.
Project Goals
Develop a proof of concept assay that could be used as the basis of a diagnostic method for stool that quantitatively detects not only the presence and relative amount of one or more of the previously described MDROs (i.e., CRE, VRE, ESBL, and/or C. difficile), but also the taxonomic components and diversity of the gut microbiome.  The approach to both MDRO detection and microbiome description may utilize a number of different existing technologic platforms and combinations thereof including, but not limited to, single or multiplex PCR platforms, 16S ribosomal RNA-encoding DNA amplification and sequencing, deep DNA sequencing, or other advanced metagenomic or metabolomic methods.
The overall objectives are to: 1) detect colonization  by one or more MDRO(s) using a molecular approach expected to yield a clinically meaningful sensitivity and specificity; 2) determine the abundance of the MDRO(s) relative to important taxonomic components of the lower intestinal microbiome (e.g., degree of dominance); 3) determine relative abundance and diversity of the important taxa of the lower intestinal microbiome to describe disruptions that may portend future near-term risk of MDRO colonization or, if already colonized, the future risk for transmission and infection and; 4) generate results with a clinically useful turnaround time.
Phase I Activities and Expected Deliverables
1.      Determine a workable strategy to achieve the above outlined goals.  
2.      Develop pertinent wet-lab protocols to identify and modify, if necessary, any existing software or bioinformatics tools necessary for interpretation, and 
3.      Demonstrate, using spiked human stool or waste clinical specimens from which MDRO have been cultured, the detection of MDROs and, using stool from antibiotic-na?ve and antibiotic-experienced patients, the ability to discern major microbiome disruptions.
Projected Phase II Activities
1.      Build-out of modular components for commercialization of a clinical assay including adaptation of assay and results interpretation for use with rectal swabs
2.      Perform a clinical demonstration study divided into two phases:
a.      Testing at-risk patients periodically throughout their hospitalization, correlating results of the combined microbiome and MDRO assay performed on a rectal swab with antibiotic and other drug exposures as well as microbiologic evidence (i.e., perform sampling) of patient skin, patient care area environment (i.e., high-touch surfaces), and healthcare worker hand contamination caused by the target MDRO. Select patient population (based on underlying clinical risk) and power the sample size to examine the capability of assay to predict ongoing risk for colonization (in the previously non-colonized) and transmission or infection events among those already colonized. No clinical or infection control intervention will be based upon assay results, observational only. The goal will be to demonstrate the predictive capability of the combined assay results of microbiome disruption and MDRO detection (and the degree of MDRO dominance in the microbiome), over and above qualitative MDRO detection alone, for the likelihood of colonization or, if already colonized, the likelihood to serve as a source for transmission.
b.      A proof of concept infection control intervention focused on enhanced environmental cleaning and glove use triggered by assay results, examining its impact on transmission and compared to either a historic (i.e., quasi-experimental) or concurrent ward, unit, or facility control.
3.      Engage either developers of an advanced probiotic or academic investigators studying fecal microbiota transplantation (under an FDA IND) to design study for future implementation in which one of these interventions is offered to patients on the basis of assay results as a means to reduce their risk for colonization and infection as well as transmission to other patients.
Impact
Having a means to monitor the level of microbiome disruption in a patient, while simultaneously detecting colonization with selected MDROs, will allow proactive identification of the infection control risk of patients, both in terms of their vulnerability to colonization with an MDRO (i.e., if they are disrupted) and their risk of transmission if they are already MDRO-colonized or (especially) if they are MDRO-dominated. Moreover, because MDROs are pathobionts, it is likely the identification of MDRO domination will become regarded as an important independent risk factor (along with others) for infection in many, if not all, patient populations. Meanwhile, microbiome restorative therapies are currently under clinical development. The data generated from assays such as this, once integrated into clinical care, will provide not only direction to antibiotic stewardship and infection control but also form the basis for an entirely new frontier of patient management. It is not an over statement that the development and use of ?microbiome disruption indexes? in patient management will revolutionize current infection control and MDRO prevention in all of healthcare.
Commercialization Potential
With the appropriate level of intellectual and fiscal capital invested into a relatively easy to use, straightforward platform with good bioinformatics support, the commercialization potential is tremendous. At least in the case of C. difficile there are already national third-party payer incentives for hospitals to reduce publically reported rates, such that it is plausible that hospitals will utilize available advanced diagnostics that stratify patient risks for colonization, transmission, and infection. In addition, it is likely that advanced probiotics and other microbiome restorative therapies will become available in the next 5-10 years and, coupled with the appropriate risk-stratifying diagnostics, these may become administered routinely to patients with microbiome disruption following antibiotic or other drug therapies.
National Center For HIV/AIDS, Viral Hepatitis, STD, and TB Prevention (NCHHSTP)
The mission of the National Center for HIV/AIDS, Viral Hepatitis, STD, and TB Prevention (NCHHSTP) is to maximize public health and safety nationally and internationally through the elimination, prevention, and control of disease, disability, and death caused by HIV/AIDS, Viral Hepatitis, other Sexually Transmitted Diseases, and Tuberculosis.
NCHHSTP Web site:  https://www.cdc.gov/nchhstp/
 
For this solicitation NCHHSTP invites Phase I proposals in the following areas:

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