Characterization of Polymyxin B-Induced Nephrotoxicity: Implications for Dosing Regimen Design
Characterization of Polymyxin B-Induced Nephrotoxicity: Implications for Dosing Regimen Design
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DOI：
10.1128/aac.00280-12
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发表时间：
2012-09-01
影响因子：
4.9
通讯作者：
Tam, Vincent H.
中科院分区：
文献类型：
--
作者：
Abdelraouf, Kamilia;Braggs, Kirk H.;Tam, Vincent H.
随着耐多药革兰氏阴性感染的日益流行，人们对全体性多粘菌素B的使用重新产生了兴趣。然而，多粘菌素B的肾毒性仍然知之甚少。本研究的目的是表征与多粘菌素B相关的肾毒性，重点是检查给药频率对肾毒性发作的影响。将Sprague-Dawley大鼠分为两组，皮下注射多粘菌素B总剂量相同，但给药频率不同（每24h给药20 mg/kg体重[q24h]或5 mg/kg q6h）。24 h比较两组肾组织药物浓度。48 h取肾组织进行组织学比较。每天测量血清肌酐，持续10天，肾毒性定义为血清肌酐显著升高（>= 2倍基线）。Kaplan-Meier分析用于比较肾毒性的发生情况。多粘菌素b引起的肾毒性表现为血清肌酐升高和急性肾小管坏死。观察到近端小管大面积损伤。q6h给药组肾脏病变更严重，药物浓度更高。q24h给药组肾毒性发作更为缓慢，这可能是由于肾组织药物浓度较低（多粘菌素B1为48.5 +/- 17.4 μ g/g，多粘菌素B1为92.1 +/- 18.1 μ g/g, P = 0.04）。多粘菌素B在肾脏的优先积累表明，摄取到肾细胞是一个非被动的过程，q24小时给药比q6小时给药的肾毒性更小。
The increasing prevalence of multidrug-resistant Gram-negative infections has led to renewed interest in the use of systemic polymyxin B. However, the nephrotoxic properties of polymyxin B are still poorly understood. The objective of this study was to characterize nephrotoxicity associated with polymyxin B, with an emphasis on examining the impact of dosing frequencies on the onset of nephrotoxicity. Sprague-Dawley rats were divided into two groups and administered the same total daily dose of polymyxin B subcutaneously but with different dosing frequencies (either 20 mg/kg of body weight every 24 h [q24h] or 5 mg/kg q6h). Drug concentrations in renal tissue were compared between the two groups at 24 h. Kidney tissues were harvested at 48 h and compared histologically. Serum creatinine was measured daily for up to 10 days, and nephrotoxicity was defined as a significant elevation in serum creatinine (>= 2x baseline). Kaplan-Meier analysis was used to compare the onset of nephrotoxicity. Polymyxin B-induced nephrotoxicity manifested as elevation in serum creatinine and acute tubular necrosis. Extensive injury of the proximal tubules was observed. The lesions were more severe and higher drug concentrations were achieved in the kidneys of the q6h dosing group. The q24h dosing group experienced a more gradual onset of nephrotoxicity, which could be attributed to the lower kidney tissue drug concentrations (48.5 +/- 17.4 mu g/g versus 92.1 +/- 18.1 mu g/g of polymyxin B1, P = 0.04). Preferential accumulation of polymyxin B in the kidneys suggests that uptake to renal cells is a nonpassive process and q24h dosing was less nephrotoxic than q6h dosing.