Department of Pharmacological & Pharmaceutical Sciences, University of Houston College of Pharmacy, 4849 Martin Luther King Boulevard, Houston, TX, USA.
Department of Pharmacy Practice & Translational Research, University of Houston College of Pharmacy, 4849 Martin Luther King Boulevard, Houston, TX, USA.
J Antimicrob Chemother. 2023 Oct 3;78(10):2435-2441. doi: 10.1093/jac/dkad246.
Aminoglycosides and polymyxins are antibiotics with in vitro activity against MDR Gram-negative bacteria. However, their clinical use is hindered by dose-limiting nephrotoxicity. 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.
Sprague Dawley rats (n = 10, both genders) were administered either amikacin (300 mg/kg) or polymyxin B (20 mg/kg) daily for 10 days. Zileuton (4 and 10 mg/kg) was delivered intraperitoneally 15 min before antibiotic administration. Blood samples were collected at baseline and daily to determine serum creatinine concentration. Nephrotoxicity was defined as a ≥2× 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 also conducted to characterize the extent of kidney injury.
Animals receiving amikacin or polymyxin B alone had nephrotoxicity rates of 90% and 100%, 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 at 4 and 10 mg/kg, respectively. Histopathology confirmed reduced kidney injury in animals receiving amikacin concomitant with zileuton.
Our pilot data suggest that zileuton has the potential to attenuate nephrotoxicity associated with last-line antibiotics. This would allow these antibiotics to treat MDR Gram-negative bacterial infections optimally without dose-limiting constraints. Further studies are warranted to optimize drug delivery and dosing in humans.
氨基糖苷类和多黏菌素具有体外抗多重耐药革兰氏阴性菌的活性。然而，其临床应用受到剂量限制的肾毒性的阻碍。本项目的目的是确定齐留通是否可以减少氨基糖苷类和多黏菌素 B 在急性肾损伤大鼠模型中的肾毒性。
Sprague Dawley 大鼠（n=10，雌雄各半）每天给予氨基糖苷类（300mg/kg）或多黏菌素 B（20mg/kg），共 10 天。齐留通（4mg/kg 和 10mg/kg）在抗生素给药前 15 分钟腹腔内给药。在基线和每天采集血样以确定血清肌酐浓度。肾毒性定义为基线血清肌酐升高≥2×。采用生存时间分析和对数秩检验比较不同队列肾毒性的发生。还进行了组织病理学分析以表征肾脏损伤的程度。
单独接受氨基糖苷类或多黏菌素 B 的动物的肾毒性发生率分别为 90%和 100%。接受辅助齐留通的动物的总发生率降低至 30%。齐留通还分别以 4mg/kg 和 10mg/kg 的剂量显著延迟了与氨基糖苷类和多黏菌素 B 相关的肾毒性的发生。组织病理学证实了接受齐留通同时接受氨基糖苷类治疗的动物的肾脏损伤减少。
我们的初步数据表明，齐留通具有减轻最后一线抗生素相关肾毒性的潜力。这将使这些抗生素能够在没有剂量限制的情况下，最佳地治疗多重耐药革兰氏阴性菌感染。需要进一步的研究来优化人类的药物输送和剂量。
