Markers of Nephrotoxicity during treatment with Antibiotic Combinations: The MONACO clinical trial

PROJECT SUMMARY: Vancomycin (VN) and piperacillin-tazobactam (PT) are two of the most used antibiotics to treat patients with severe infection. The emergence of data linking combined treatment with VN+PT to acute kidney injury (AKI) is thus a major safety concern. AKI, the syndrome of rapid kidney function decline, is associated with increased risk of death and a nearly 8-fold higher risk of chronic kidney disease. Given these potential risks, many health systems have implemented initiatives to avoid VN+PT despite its therapeutic utility. However, whether VN+PT is truly nephrotoxic remains uncertain due to the use of creatinine – a functional biomarker with poor sensitivity and specificity for tubular injury – as the standard biomarker to evaluate nephrotoxicity. Animal models of the interaction suggest that PT might actually reduce VN mediated kidney injury when evaluated with non-creatinine biomarkers of kidney injury. Hypothesizing associatedAKI represents pseudotoxicity– that VN+PT inhibition of creatinine secretion without kidney parenchymal injury – we showed that VN+PT was associated with significantly increased creatinine concentrations, but not with change in cystatin C (Cys-C), a kidney function biomarker unaffected by tubular secretion. Although these results may have practice changing implications, the small sample size and observational design of the study preclude definitive conclusions. Beyond limiting our understanding of VN+PT associated AKI, the poor diagnostic characteristics of creatinine precludes differentiation of VN nephrotoxicity from other types of AKI subtypes; and the delayed change in creatinine relative to tissue injury limits the potential for mitigating AKI severity through timely dosage adjustment. Although biomarkers directly reflective of cellular stress, cellular damage, and renal reserve have shown promise in the context of critical illness or cardiac surgery, their utility for monitoring nephrotoxic drugs remains unclear. We central handling; molecular will leverage our established acute care research infrastructure to examine two hypotheses: 1) VN+PT associated AKI is a pseudotoxicity manifested by isolated effects on creatinine and 2) the temporal dynamics of a broad panel of kidney biomarkers can be used to create a signature of VN nephrotoxicity. randomized controlled trialWe will test these hypotheses in a comparing VN+PT to VN+cefepime (CP) – two standard of care antibiotic combinations in acutely ill patients with infection. We will obtain serial measures of biomarkers of kidney function and injury to examine comparative nephrotoxicity. This proposal will provide definitive evidence on the heavily debated kidney safety of the essential VN+PT combination. In addition, we will leverage a rich dataset of kidney biomarkers to develop a molecular signature of VN nephrotoxicity, with the aim of establishing a new paradigm for kidney function monitoring in patients treated with nephrotoxic drugs.