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Decoding the clinical impact of the recent evolution of metronidazole resistance on Clostridium difficile infection.

Award Number: R01AI139261
ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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PROJECT SUMMARY/ABSTRACT Clostridium difficile infection (CDI) is a major hospital-acquired illness that causes severe morbidity and mortality. In 2011, the CDC reported that there were 453,000 cases of CDI in the United States, with 29,000 deaths. The emergence of epidemic strains, notably NAP1/027, has considerably increased the prevalence and severity of the disease. This clade of C. difficile developed resistance to both metronidazole (a CDI medication) and fluoroquinolones (commonly used antibiotics). As a result, two selection forces drove the worldwide spread of epidemic strains. Now the strains are increasingly becoming resistant to vancomycin, the antibiotic of choice for CDI. Vancomycin is an important first-line treatment for CDI, and increased prescribing of this antibiotic has raised selection pressures. Vancomycin resistance is increasingly more prevalent in epidemic strains, especially NAP1/027, and our study revealed that these strains are spreading internationally. This is concerning since this lineage is associated with severe illness and rapid transmission in hospitals. Preliminary findings indicate that patients infected with vancomycin resistant strains are twice as likely to have poor clinical outcomes. Genome analyses indicate these strains are developing primary and secondary resistance mechanisms that allow them to persist in drug concentrations predicted to occur in the colons of patients. Critical questions remain to understand this emerging form of C. difficile, which address in three cohesive aims. In one goal, we perform clinical studies and epidemiological research using biobanked samples and patient metadata to understand how these emerging pathogens affect clinical outcomes and disease characteristics, during vancomycin therapy. It is supported by clinical reflective in vitro and animas models of CDI. In the second goal, the strains will be genetically characterized to delineate genetic variations that promote treatment failures in patients. These genetic signatures will be molecularly validated in the lab and used in population-based analyses of public genomes to understand global patterns of resistance among patient isolates. Lastly, given there are few treatment options for CDI, other antibiotic strategies will be investigated to provide additional coverage of organisms prone to vancomycin to fail. The outcome of this research will be delineation of genetic variations that evolve in C. difficile that cause therapeutic failure. This will lay the foundation for molecular and genomic diagnostics to rapidly detect these strains to improve prescribing approaches for CDI patients. Public health. This study has significant implications for the diagnosis and treatment of CDI, a disease that imposes a major public health and economic burden in the United States.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2024 ( Subtotal = $691,273 )
2024	2024	TEXAS A & M UNIVERSITY SYSTEM HEALTH SCIENCE CENTER	6003 TAMU	COLLEGE STATION	TX	77843	BRAZOS	USA	Allergy and Infectious Diseases Research	000	6	1/23/2024	NON-COMPETING CONTINUATION	$691,273
														Subtotal = $691,273

Issue Date FY: 2023 ( Subtotal = $796,393 )
2023	2023	TEXAS A & M UNIVERSITY SYSTEM HEALTH SCIENCE CENTER	6003 TAMU	COLLEGE STATION	TX	77843	BRAZOS	USA	Allergy and Infectious Diseases Research	003	5	6/26/2023	COMPETING CONTINUATION	$160,377
2023	2023	TEXAS A & M UNIVERSITY SYSTEM HEALTH SCIENCE CENTER	6003 TAMU	COLLEGE STATION	TX	77843	BRAZOS	USA	Allergy and Infectious Diseases Research	001	5	2/22/2023	COMPETING CONTINUATION	$796,393
2023	2021	TEXAS A & M UNIVERSITY SYSTEM HEALTH SCIENCE CENTER	6003 TAMU	COLLEGE STATION	TX	77843	BRAZOS	USA	Allergy and Infectious Diseases Research	000	4	2/10/2023	NON-COMPETING CONTINUATION	$0
2023	2021	TEXAS A & M UNIVERSITY SYSTEM HEALTH SCIENCE CENTER	6003 TAMU	COLLEGE STATION	TX	77843	BRAZOS	USA	Allergy and Infectious Diseases Research	002	4	6/26/2023	NON-COMPETING CONTINUATION	-$160,377
														Subtotal = $796,393

Issue Date FY: 2021 ( Subtotal = $675,085 )
2021	2021	TEXAS A&M UNIVERSITY SYSTEM, THE	8441 RIVERSIDE PARKWAY BLDG 1 STE 3100	BRYAN	TX	77807	BRAZOS	USA	Allergy and Infectious Diseases Research	000	4	7/14/2021	NON-COMPETING CONTINUATION	$675,085
														Subtotal = $675,085

Issue Date FY: 2020 ( Subtotal = $654,080 )
2020	2020	TEXAS A&M UNIVERSITY SYSTEM, THE	8441 RIVERSIDE PARKWAY BLDG 1 STE 3100	BRYAN	TX	77807	BRAZOS	USA	Allergy and Infectious Diseases Research	000	3	7/13/2020	NON-COMPETING CONTINUATION	$654,080
														Subtotal = $654,080

Issue Date FY: 2019 ( Subtotal = $696,716 )
2019	2019	TEXAS A&M UNIVERSITY SYSTEM, THE	8441 RIVERSIDE PARKWAY BLDG 1 STE 3100	BRYAN	TX	77807	BRAZOS	USA	Allergy and Infectious Diseases Research	000	2	8/2/2019	NON-COMPETING CONTINUATION	$696,716
														Subtotal = $696,716

Issue Date FY: 2018 ( Subtotal = $647,212 )
2018	2018	TEXAS A&M UNIVERSITY SYSTEM,THE	200 TECHNOLOGY WAY, STE 2079	COLLEGE STATION	TX	77845	BRAZOS	USA	Allergy and Infectious Diseases Research	000	1	8/20/2018	NEW	$647,212
														Subtotal = $647,212

Grand Total All Awards = $4,160,759

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Decoding the clinical impact of the recent evolution of metronidazole resistance on Clostridium difficile infection.

Award Number: R01AI139261

ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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