2542. Attenuation of Polymyxin and Aminoglycoside-Associated Nephrotoxicity

Abstract Background The clinical use of aminoglycosides and polymyxins to treat multidrug-resistant Gram-negative bacterial infections is hindered by dose-limiting nephrotoxicity. Recently, there has been increased interest in reducing the nephrotoxic potential of these antibiotics to combat the antimicrobial resistance crisis. We identified zileuton, an FDA-approved anti-inflammatory drug, via a virtual screen indicating that it has desirable properties as a potential nephroprotectant. The objective of this project was to determine if zileuton can reduce nephrotoxicity associated with amikacin and polymyxin B in a rat model of acute kidney injury. Methods Sprague-Dawley rats (n=10, both genders) were administered either amikacin (300 mg/kg) or polymyxin B (20 mg/kg) daily for 10 days. Doses were chosen based on prior pharmacokinetic studies to achieve a systemic exposure comparable to that in humans after a standard dose. Zileuton (4 and 10 mg/kg) was delivered intraperitoneally 15 minutes before antibiotic administration each day. Blood samples were collected at baseline and daily to determine serum creatinine concentration. Nephrotoxicity was defined as a ≥ 2x elevation of baseline serum creatinine. Time-to-event analysis and log rank test were used to compare the onset of nephrotoxicity in different cohorts. Histopathological analysis was conducted to characterize the extent of renal injury. Results Animals receiving amikacin or polymyxin B alone had nephrotoxicity rates of 90% and 100% within 10 days, respectively. The overall rate was reduced to 30% in animals receiving adjuvant zileuton. The onset of nephrotoxicity associated with amikacin and polymyxin B was also significantly delayed by zileuton 4 mg/kg and 10 mg/kg, respectively. Additionally, histopathology confirmed reduced renal injury in animals receiving concomitant zileuton. Conclusion This pilot study suggests that zileuton has the potential to attenuate nephrotoxicity associated with last-line antibiotics. This would allow these antibiotics to treat multidrug-resistant Gram-negative bacterial infections optimally without dose-limiting constraints. Further studies are warranted to optimize drug delivery and characterize pharmacokinetics to correlate with clinical dosing in humans. Disclosures All Authors: No reported disclosures