NIH grant: Strategies to Avoid Drug Induced Kidney Injury in the Treatment of Multi-Drug Resistant Pathogens (1R21AI190716-01A1)

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NIH grant 1R21AI190716-01A1: Strategies to Avoid Drug Induced Kidney Injury in the Treatment of Multi-Drug Resistant Pathogens
Institute: {'code': 'AI', 'abbreviation': 'NIAID', 'name': 'National Institute of Allergy and Infectious Diseases', 'admin_org_id': '12500003', 'admin_funding_url': ''}. PI: Marc Howard Scheetz. Award: $296150.
Start: 2026-06-24T00:00:00.
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.

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