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Strategies to Avoid Drug Induced Kidney Injury in the Treatment of Multi-Drug Resistant Pathogens

Award Number: R21AI190716
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: 06/24/2026
PERIOD OF PERFORMANCE END DATE: 05/31/2028

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Strategies to Avoid Drug Induced Kidney Injury in the Treatment of Multi-Drug Resistant Pathogens - Project Abstract: There is a fundamental need to improve treatment for methicillin-resistant Staphylococcus aureus. We will define how dynamic toxicity thresholds change for vancomycin with co-nephrotoxins and nephroprotectants for adults and children using richly collected clinical data and age-appropriate animal models. Dynamic toxicity thresholds will ultimately enable precision dosing strategies for safe and effective vancomycin exposures. The long-term goal of this research is to improve the kidney safety profile of critical antibiotics. Vancomycin is the most used hospital antibiotic and causes drug induced kidney injury (DIKI). The objectives of this proposal are to: 1) leverage age-specific animal models to define the `dynamic toxicity threshold' in the setting of concomitant therapies for adults and children and 2) Link data from the bench to the bedside and simulate dosing strategies that ensure safe and effective therapy in both adults and children. The central hypothesis is that co-nephrotoxins lower the vancomycin toxicity threshold for DIKI. Understanding this threshold will allow clinicians to use Precision Dosing and nephroprotectant strategies to decrease DIKI. Prior research shows: A) Specific vancomycin concentrations cause DIKI. B) Kidney injury molecule-1 (KIM-1) and other biomarkers are sensitive and specific for AKI. C) Our rat model for vancomycin AKI links to human outcomes, serving as a translational platform. We AIM to quantify dynamic exposure:toxicity threshold changes for vancomycin DIKI +/- an exemplar nephrotoxin, and +/- an exemplar nephroprotectant, and link to rat models. Aim 1 uses flucloxacillin (co-nephrotoxin) and protamine (nephroprotectant) to create dynamic toxicity thresholds. Testing all drugs simultaneously will address if a nephroprotectant can restore the therapeutic window for vancomycin with a co-nephrotoxin. We will bridge to human by linking our rat model to CAMERA2, a large vancomycin trial. Aim 2 quantifies dynamic exposure:toxicity threshold changes for vancomycin +/- vasopressors in an age-appropriate rat model. Importantly, we will adapt our well-characterized adult rat model to a juvenile rat model (analog of a 2-year-old patient). Using vancomycin pharmacokinetics and kidney injury biomarkers, we will link the juvenile rat model to children with multiple organ dysfunction syndrome from our highly unique AMPLE study (R01HD103755). This project will be innovative because 1) Dynamic toxicity thresholds are novel and will enable Precision Medicine and 2) Adapting our rat model to the pediatric environment facilitates bridging to one of the largest clinical datasets of vancomycin pharmacodynamics in children. These contributions will be significant because “real world” patients often receive co-nephrotoxins; a platform is necessary to define injury risk outside of clinical trial scenarios that are not relevant for most patients. This proposal addresses the NIH mission to `innovate research strategies' to `cure human diseases' by creating a platform that can funnel successful pre-clinical approaches to 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: 2026 ( Subtotal = $296,150 )
2026	2026	MIDWESTERN UNIVERSITY	555 31ST ST	DOWNERS GROVE	IL	60515	DUPAGE	USA	Allergy and Infectious Diseases Research	000	1	6/25/2026	NEW	$296,150
														Subtotal = $296,150

Grand Total All Awards = $296,150

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Strategies to Avoid Drug Induced Kidney Injury in the Treatment of Multi-Drug Resistant Pathogens

Award Number: R21AI190716

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: 06/24/2026

PERIOD OF PERFORMANCE END DATE: 05/31/2028

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