Couture M, Simard M, Gourde P, Lessard C, Gurnani K, Lin L, Carrier D, Bergeron M G, Beauchamp D
Laboratoire et Service d'Infectiologie, Université Laval, Ste-Foy, Québec, Canada.
Antimicrob Agents Chemother. 1994 Apr;38(4):742-9. doi: 10.1128/AAC.38.4.742.
The lipopeptidic antibiotic daptomycin is reported to reduce experimental tobramycin nephrotoxicity (D. Beauchamp, M. Pellerin, P. Gourde, M. Pettigrew and M. G. Bergeron, Antimicrob. Agents Chemother. 34:139-147, 1990; C. A. Wood, H. C. Finkbeiner, S. J. Kohlhepp, P. W. Kohnen, and D. C. Gilbert, Antimicrob. Agents Chemother. 33:1280-1285, 1989). In an attempt to explain these results, the in vivo and in vitro interactions between daptomycin and tobramycin were studied. Tobramycin alone and preincubated with negatively charged phospholipid bilayers (liposomes) was dialyzed against increasing concentrations of daptomycin in buffer at pH 5.4. A significant drop in the concentration of tobramycin was observed when daptomycin was added to the opposite half cells. Furthermore, daptomycin induced a concentration-dependent release of lipid-bound tobramycin. Gold labeling experiments showed that daptomycin could be incorporated into phospholipid layers. Female Sprague-Dawley rats were treated with daptomycin alone, with tobramycin alone, or with the combination over 2 to 10 days. Levels of daptomycin and tobramycin in serum were similar in all groups. The levels of tobramycin in the renal cortex increased significantly with time and, on day 10, reached values of 654 +/- 122 and 844 +/- 298 micrograms/g of tissue (mean +/- standard deviation; not significant) in animals treated with tobramycin and the combination of daptomycin-tobramycin, respectively. No significant difference was observed in the levels of tobramycin in the kidneys between animals treated with tobramycin or the daptomycin-tobramycin combination at any time. By contrast, daptomycin levels were significantly higher in the renal cortexes of animals treated with daptomycin-tobramycin in comparison with those in the renal cortexes of animals treated with daptomycin alone on days 6,8, and 10 (P < 0.01). For immunogold labeling studies, animals were killed 4 h after a single injection of daptomycin alone or daptomycin in combination with tobramycin. Daptomycin was found throughout the matrixes of the lysosomes of proximal tubular cells of animals treated with daptomycin alone. In animals treated with the combination of daptomycin and tobramycin, daptomycin was associated with intralysosomal myeloid bodies. Our results suggest that daptomycin might attenuate experimental aminoglycoside nephrotoxicity by interacting with the aminoglycoside, perhaps electrostatically, and thereby protecting intracellular targets of toxicity.
据报道，脂肽类抗生素达托霉素可降低实验性妥布霉素肾毒性（D. 博尚、M. 佩勒林、P. 古尔迪、M. 佩蒂格鲁和M. G. 伯杰龙，《抗菌药物与化疗》34:139 - 147，1990年；C. A. 伍德、H. C. 芬克拜纳、S. J. 科尔赫普、P. W. 科嫩和D. C. 吉尔伯特，《抗菌药物与化疗》33:1280 - 1285，1989年）。为解释这些结果，对达托霉素与妥布霉素在体内和体外的相互作用进行了研究。将单独的妥布霉素以及预先与带负电荷的磷脂双层（脂质体）预孵育的妥布霉素，在pH 5.4的缓冲液中与浓度不断增加的达托霉素进行透析。当向另一半细胞中加入达托霉素时，观察到妥布霉素浓度显著下降。此外，达托霉素诱导了脂质结合妥布霉素的浓度依赖性释放。金标记实验表明达托霉素可掺入磷脂层。对雌性斯普拉格 - 道利大鼠单独给予达托霉素、单独给予妥布霉素或联合用药2至10天。所有组血清中的达托霉素和妥布霉素水平相似。肾皮质中的妥布霉素水平随时间显著升高，在第10天，单独给予妥布霉素和联合给予达托霉素 - 妥布霉素的动物组织中，妥布霉素水平分别达到654±122和844±298微克/克组织（平均值±标准差；无显著差异）。在任何时间，单独给予妥布霉素或联合给予达托霉素 - 妥布霉素的动物肾脏中，妥布霉素水平均未观察到显著差异。相比之下，在第6、8和10天，联合给予达托霉素 - 妥布霉素的动物肾皮质中的达托霉素水平显著高于单独给予达托霉素的动物肾皮质中的达托霉素水平（P<0.01）。对于免疫金标记研究，在单独单次注射达托霉素或达托霉素与妥布霉素联合注射后4小时处死动物。在单独给予达托霉素的动物近端肾小管细胞溶酶体基质中均发现了达托霉素。在联合给予达托霉素和妥布霉素的动物中，达托霉素与溶酶体内的髓样小体相关。我们的结果表明，达托霉素可能通过与氨基糖苷类药物相互作用（可能是静电相互作用）来减轻实验性氨基糖苷类肾毒性，从而保护细胞内的毒性靶点。
