1569. A Translational Model to Assess the Impact of Polymyxin B Dose Fractionation on Kidney Injury

BACKGROUND: Progression of antimicrobial resistance has revived Polymyxin B (PB) use in clinical practice. Dose-dependent acute kidney injury (AKI) limits its clinical use. It is unclear whether dose fractionation of total daily dose can lessen kidney injury. We assessed the role of PB fractionation on AKI in a translational model that employs sensitive urine biomarkers qualified by the FDA. METHODS: Male Sprague–Dawley rats received 12 mg/kg/day PB subcutaneously for 3 days or equal-volume normal saline (NS). PB was administered in 3 separate fractionated daily doses: 12 mg/kg daily (QD), 6 mg/kg twice daily (BID), and 4 mg/kg thrice daily (TID). Staggered blood sampling was done on days 1 to 4 and 24 hour urine was collected at baseline, on days 1, 2, and 3. Plasma creatinine (Cr) was quantified using LCMS/MS, and 24 hour urinary biomarkers (KIM1, OPN, CLN, calbindin, GSTα, IP-10, TIMP-1, and VEGF) were assayed with MILLIPLEX Rat Kidney Toxicity Magnetic Bead Panel. Mixed-effects models were used. RESULTS: A total of 32 rats contributed to the study data. Mean Cr were constant across groups over time (Figure 1, P = 0.18). For NS group, all biomarkers remained at baseline throughout study. Significant differences were seen for fractionation schemes for KIM1 (P = 0.02), CLN (P = 0.03), IP-10 (0.007) and TIMP-1 (P = 0.04). The differences for KIM1, IP-10, and TIMP-1 were driven by higher observed values in TID than those of BID as early as day 1 (P < 0.04). Furthermore, CLN was elevated for TID when compared with BID at baseline (P = 0.048). Similarly, TID group had the highest (but non-significant) elevations for IP-10 and TIMP-1 compared with QD on study days. Amongst all urine biomarkers, KIM1 in TID exhibited the most rapid rise from baseline to day 2 (Figure2, P < 0.0001). CONCLUSION: In this translational model in which a single total daily dose was fractionated, sensitive urinary biomarkers indicated that TID dosing was worse than BID or QD dosing; dose fractionation of PB may lead to increased AKI. In addition, KIM1 rose rapidly as an early marker for AKI. Further efforts are needed to investigate the PK-TD relationship of PB in order to decrease AKI. [Image: see text] [Image: see text] DISCLOSURES: All authors: No reported disclosures.