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.
