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Next-generation combination dosing strategies to combat resistant Acinetobacter baumannii

Award Number: R01AI130185
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: 11/08/2017
PERIOD OF PERFORMANCE END DATE: 10/31/2023

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Next-generation combination dosing strategies to combat resistant Acinetobacter baumannii - Project Summary/Abstract Due to a lack of effective antibiotics, Acinetobacter baumannii is one of the six most dangerous bacterial “superbugs” that cause one of the world’s three most serious human health threats. Exacerbating this is a dramatic decline in the number of new antibiotics effective against A. baumannii, which can cause serious bloodstream, respiratory tract, wound, and other infections with very high morbidity and up to 80% mortality. Carbapenem (a member of the β-lactam class of antibiotics)-resistant (CR) A. baumannii infections cost the U.S. health-care system $389 million per year. As A. baumannii isolates resistant to most or all antibiotics in monotherapy are rapidly increasing in the United States and worldwide, monotherapy is clearly no longer viable. With clinicians therefore being forced to use empiric, non-optimized combinations that may fail and lead to even more resistance, the development of novel dosing strategies that use antibiotics in efficacious combinations is critical. This project will yield promising combination dosing schemes to combat multidrug- resistant (MDR) and pandrug-resistant (PDR) A. baumannii. Our preliminary data show that combining a carbapenem with an aminoglycoside antibiotic is highly effective against MDR A. baumannii. To rationally optimize therapies, this project will provide the first systematic data on the binding of β-lactam antibiotics to their bacterial target receptors in A. baumannii (Aim 1, stage 1). This will identify the optimal sets of bacterial target receptors that should be bound and inactivated by β-lactam antibiotics and will greatly improve optimal β-lactam therapies. In stage 2 of Aim 1, in vitro infection models will assess bacterial killing and resistance prevention for innovative two- and three-drug combination dosing strategies against MDR and PDR A. baumannii. These in vitro models can simulate antibiotic concentration-time profiles that mirror those in patients. Combination regimens to be tested include simultaneous and sequential dosing with normal and short-course aminoglycoside therapy. The ability of novel broad-spectrum β-lactamase inhibitors to significantly enhance the activity of β-lactam antibiotics in A. baumannii will be assessed. In Aim 2, the kinetics of target receptor binding by β-lactams will be evaluated, and transcriptomic and genomic approaches applied to elucidate the mechanistic basis for resistance prevention, using bacterial samples from Aim 1. Next, in Aim 3, data on target receptor binding, drug concentrations, bacterial killing, resistance prevention, and resistance mechanisms will be used to develop new mechanism-based models. Applying these models will rationally optimize two- and three-drug combination dosing strategies that better target MDR and PDR A. baumannii. In Aim 4, these regimens will be validated prospectively via dynamic in vitro and murine pneumonia models with an intact or compromised immune system. This project holds excellent promise for developing efficacious and robust combination dosing strategies against MDR and PDR A. baumannii for testing in future clinical trials.


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 = $0 )
2024	2022	UNIVERSITY OF FLORIDA	1523 UNION RD RM 207	GAINESVILLE	FL	32611	ALACHUA	USA	Allergy and Infectious Diseases Research	000	5	6/27/2024	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2022 ( Subtotal = $657,531 )
2022	2022	UNIVERSITY OF FLORIDA	1523 UNION RD RM 207	GAINESVILLE	FL	32611	ALACHUA	USA	Allergy and Infectious Diseases Research	000	5	10/20/2021	NON-COMPETING CONTINUATION	$657,531
														Subtotal = $657,531

Issue Date FY: 2021 ( Subtotal = $674,050 )
2021	2021	UNIVERSITY OF FLORIDA	1523 UNION RD RM 207	GAINESVILLE	FL	32611	ALACHUA	USA	Allergy and Infectious Diseases Research	000	4	10/23/2020	NON-COMPETING CONTINUATION	$674,050
														Subtotal = $674,050

Issue Date FY: 2020 ( Subtotal = $649,808 )
2020	2020	UNIVERSITY OF FLORIDA	1523 UNION RD RM 207	GAINESVILLE	FL	32611	ALACHUA	USA	Allergy and Infectious Diseases Research	000	3	11/6/2019	NON-COMPETING CONTINUATION	$649,808
														Subtotal = $649,808

Issue Date FY: 2019 ( Subtotal = $688,839 )
2019	2019	UNIVERSITY OF FLORIDA	1523 UNION RD RM 207	GAINESVILLE	FL	32611	ALACHUA	USA	Allergy and Infectious Diseases Research	000	2	10/24/2018	NON-COMPETING CONTINUATION	$688,839
														Subtotal = $688,839

Issue Date FY: 2018 ( Subtotal = $739,771 )
2018	2018	UNIVERSITY OF FLORIDA	207 GRINTER HALL	GAINESVILLE	FL	32611	ALACHUA	USA	Allergy and Infectious Diseases Research	000	1	11/8/2017	NEW	$739,771
2018	2018	UNIVERSITY OF FLORIDA	1523 UNION RD RM 207	GAINESVILLE	FL	32611	ALACHUA	USA	Allergy and Infectious Diseases Research	001	1	1/31/2018	NEW	$0
														Subtotal = $739,771

Grand Total All Awards = $3,409,999

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Next-generation combination dosing strategies to combat resistant Acinetobacter baumannii

Award Number: R01AI130185

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: 11/08/2017

PERIOD OF PERFORMANCE END DATE: 10/31/2023

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