A Randomized Clinical Trial of Continuous vs. Intermittent Infusion Vancomycin: Effects on Measured GFR and Kidney Injury Biomarkers

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PROJECT SUMMARY/ABSTRACT Vancomycin is the most commonly administered antibiotic in hospitalized patients, and a mainstay treatment option for empiric and definitive therapy of gram-positive infections, particularly methicillin-resistant Staphylococcus aureus (MRSA). Patients receiving vancomycin are at risk of drug-associated acute kidney injury (DA-AKI), which occurs in 5-43% of patients. Experimental preclinical data and observational clinical data from our group indicate that the administration of vancomycin via continuous as opposed to intermittent infusion (the standard of care in most institutions) reduces urinary markers of kidney injury and leads to less DA-AKI. In order to translate these findings from the rat model, this application proposes a randomized, open- label, clinical trial of continuous versus intermittent infusion vancomycin in hospitalized patients already prescribed vancomycin by their treating physician in order to evaluate the change in kidney function and injury between the two infusion strategies. Given the known limitations of serum creatinine in assessing DA-AKI, this proposal includes measured glomerular filtration rate (mGFR) using iohexol, the gold-standard index of kidney function, and other biomarkers of kidney injury and function to work toward the overall objective of testing the impact of infusion strategy (continuous versus intermittent) on kidney function. Our central hypothesis is that vancomycin administered as a continuous versus intermittent infusion results in less DA-AKI as assessed by mGFR and kidney injury biomarkers. To test this hypothesis, the following specific aims are proposed: (1) Determine if patients randomized to receive vancomycin administered via intermittent infusion experience greater reductions in mGFR, assessed using the gold standard plasma iohexol clearance, in the 72 hours after therapy initiation compared to continuous infusion, (2) Determine if patients randomized to receive vancomycin administered via intermittent infusion demonstrate greater elevations in plasma (cystatin C) and urinary (kidney injury molecule-1, clusterin, and osteopontin) kidney biomarkers of injury and function in the 72 hours after therapy initiation compared to continuous infusion, and (3) Compare the pharmacokinetic target attainment, clinical safety, and tolerability of infusion strategy in patients randomized to receive vancomycin via continuous vs. intermittent infusion. Given the millions of patients that receive vancomycin annually in the United States for the treatment of MRSA or other gram-positive infections, the proposal aligns with NIAID’s mission of better treating infectious diseases by optimizing the risk-benefit profile of this antibiotic. Testing this hypothesis is crucial to translate the preclinical findings to patients, as well as determine if larger, definitive trials are needed to test if infusion strategy improves outcomes, including safety, with vancomycin therapy.