Thibault N, Grenier L, Simard M, Bergeron M G, Beauchamp D
Laboratoire et Service d'Infectiologie, Centre de Recherche du Centre Hospitalier de l'Université Laval, Ste-Foy, Québec, Canada.
Life Sci. 1995;56(22):1877-87. doi: 10.1016/0024-3205(95)00162-y.
Daptomycin was previously shown to reduce gentamicin renal toxicity and this toxicity was not delayed by the concomitant injection of daptomycin (Thibault N., L. Grenier, M. Simard, M. G. Bergeron, and D. Beauchamp, Antimicrob. Agents Chemother., 38 1027-1035 (1994)). The protective effect of daptomycin against gentamicin toxicity was evaluated in 96 female Sprague-Dawley rats. Normal and nephrectomized rats were treated with saline (NaCl, 0.9%), gentamicin (30 mg/kg/12 hrs, i.p.), daptomycin (10 mg/kg/12 hrs, s.c.) or with a combination of daptomycin plus gentamicin during 4 and 10 days. On day 4, gentamicin and daptomycin cortical levels were higher in nephrectomized gentamicin-daptomycin-treated rats (p < 0.05) as compared to all other groups. The accumulation of gentamicin or daptomycin in nephrectomized gentamicin-daptomycin-treated or gentamicin-saline-treated rats was higher on day 4 (p < 0.01) than on day 10. Other parameters such as the sphingomyelinase activity in the renal cortex, the serum creatinine, and the histopathology showed significantly fewer changes in daptomycin-gentamicin-treated rats as compared to animals given gentamicin alone. On the other hand, the protection of daptomycin was less extensive in nephrectomized rats as compared to normal rats. Daptomycin and gentamicin were localized in the lysosomes of proximal tubular cells of animals treated with daptomycin and gentamicin given alone or in combination. These results suggest that daptomycin protects against gentamicin toxicity in nephrectomized rats but to a lesser extent than in normal rats.
先前的研究表明，达托霉素可降低庆大霉素的肾毒性，且同时注射达托霉素并不会延迟这种毒性（蒂博 N.、L. 格雷尼尔、M. 西马尔、M. G. 伯杰龙和 D. 博尚，《抗菌药物化疗》，38: 1027 - 1035 (1994)）。在96只雌性斯普拉格 - 道利大鼠中评估了达托霉素对庆大霉素毒性的保护作用。正常大鼠和肾切除大鼠在4天和10天内分别接受生理盐水（0.9%氯化钠）、庆大霉素（30毫克/千克/12小时，腹腔注射）、达托霉素（10毫克/千克/12小时，皮下注射）或达托霉素加庆大霉素联合治疗。在第4天，与所有其他组相比，肾切除且接受庆大霉素 - 达托霉素治疗的大鼠肾皮质中庆大霉素和达托霉素的水平更高（p < 0.05）。在第4天，肾切除且接受庆大霉素 - 达托霉素治疗或庆大霉素 - 生理盐水治疗的大鼠中庆大霉素或达托霉素的蓄积量高于第10天（p < 0.01）。与单独给予庆大霉素的动物相比，其他参数如肾皮质中的鞘磷脂酶活性、血清肌酐和组织病理学显示，接受达托霉素 - 庆大霉素治疗的大鼠变化明显较少。另一方面，与正常大鼠相比，达托霉素在肾切除大鼠中的保护作用范围较小。单独或联合给予达托霉素和庆大霉素治疗的动物中，达托霉素和庆大霉素定位于近端肾小管细胞的溶酶体中。这些结果表明，达托霉素可保护肾切除大鼠免受庆大霉素毒性的影响，但程度低于正常大鼠。
