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Mechanisms of cefiderocol nonsusceptibility and resistance evolution in carbapenem-resistant pathogens

Award Number: R01AI175440
ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/01/2024
PERIOD OF PERFORMANCE END DATE: 08/31/2029

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Mechanisms of cefiderocol nonsusceptibility and resistance evolution in carbapenem-resistant pathogens - PROJECT SUMMARY The continuing emergence and rapid dissemination of antibiotic-resistant pathogens are becoming a major threat to public health. Infections caused by carbapenem-resistant Enterobacterales and carbapenem-resistant Acinetobacter, which are difficult to treat, were recognized as one of the urgent threats among patients in medical facilities. Serious infections caused by antibiotic-resistant pathogens are associated with higher rates of morbidity and mortality and contribute to significant economic costs. Cefiderocol, which received FDA approval in 2019, is a novel siderophore-conjugated cephalosporin with expanded activity against carbapenem-resistant Gram- negative pathogens including strains that produce serine carbapenemases and metallo-β-lactamases. Cefiderocol-nonsusceptible isolates were reported in surveillance studies but the resistance mechanisms are largely unknown on many occasions. Antimicrobial heteroresistance describes a phenomenon where subpopulations of genetically homogeneous bacteria exhibit a range of susceptibilities to a particular antibiotic. Heteroresistance has considerable clinical relevance because antibiotic treatment may select more resistant populations. It is considered an important factor contributing to unexplained antibiotic treatment failure. Heteroresistance has been reported in various bacterial species to many classes of antibiotics. However, there is a lack of thorough research studying cefiderocol heteroresistance, the underlying mechanisms, and its clinical relevance. The overall goal of the proposed project is to study preexisting cefiderocol resistance and heteroresistance without prior cefiderocol exposure and the evolution of cefiderocol resistance after cefiderocol exposure in vitro and in patients. In Aim 1, we will investigate preexisting cefiderocol resistance and heteroresistance mechanisms in clinically isolated carbapenem-resistant Gram-negative pathogens. In Aim 2, we will study in vitro and clinical evolution of cefiderocol resistance following cefiderocol exposure, and characterize isolates with reduced cefiderocol susceptibility.


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: 2026 ( Subtotal = $11,280 )
2026	2025	OHIO STATE UNIVERSITY, THE	1960 KENNY RD	COLUMBUS	OH	43210	FRANKLIN	USA	Allergy and Infectious Diseases Research	001	3	1/21/2026	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$739,974
2026	2025	UNIVERSITY OF ARKANSAS FOR MEDICAL SCIENCES	4301 W MARKHAM ST	LITTLE ROCK	AR	72205	PULASKI	USA	Allergy and Infectious Diseases Research	000	2	1/20/2026	NON-COMPETING CONTINUATION	-$728,694
														Subtotal = $11,280

Issue Date FY: 2025 ( Subtotal = $728,695 )
2025	2025	UNIVERSITY OF ARKANSAS FOR MEDICAL SCIENCES	4301 W MARKHAM ST	LITTLE ROCK	AR	72205	PULASKI	USA	Allergy and Infectious Diseases Research	000	2	8/26/2025	NON-COMPETING CONTINUATION	$728,695
														Subtotal = $728,695

Issue Date FY: 2024 ( Subtotal = $728,695 )
2024	2024	UNIVERSITY OF ARKANSAS FOR MEDICAL SCIENCES	4301 W MARKHAM ST	LITTLE ROCK	AR	72205	PULASKI	USA	Allergy and Infectious Diseases Research	000	1	8/29/2024	NEW	$728,695
														Subtotal = $728,695

Grand Total All Awards = $1,468,670

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Mechanisms of cefiderocol nonsusceptibility and resistance evolution in carbapenem-resistant pathogens

Award Number: R01AI175440

ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 09/01/2024

PERIOD OF PERFORMANCE END DATE: 08/31/2029

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