Strategies to avoid drug induced kidney injury in the treatment of multi-drug resistant pathogens

The National Institute of Allergy and Infectious Diseases awarded Midwestern University $296,150 on June 24, 2026, under the Allergy and Infectious Diseases Research program (CFDA 93.855) to develop strategies reducing drug-induced kidney injury from vancomycin, the most widely used hospital antibiotic for methicillin-resistant Staphylococcus aureus.

The research defines dynamic toxicity thresholds for vancomycin exposure in the presence of co-nephrotoxins and nephroprotectants across adult and pediatric populations using clinical data and age-appropriate animal models. The work aims to enable precision dosing strategies that maintain safe and effective vancomycin treatment while minimizing kidney injury. The project leverages rat models of vancomycin-induced acute kidney injury and uses exemplar compounds—flucloxacillin as a co-nephrotoxin and protamine as a nephroprotectant—to quantify how concomitant therapies alter vancomycin's toxicity threshold and whether nephroprotectants can restore the therapeutic window when used with co-nephrotoxins.

Performance occurs in Downers Grove, Illinois, with a period of performance from June 24, 2026, through May 31, 2028. The Children's Hospital of Philadelphia Research Institute serves as a sub-recipient, providing data, data analysis, and result interpretation to ensure the pediatric component receives rigorous attention. The assistance type is a Project Grant.

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.