Jiang Meiyan, Karasawa Takatoshi, Steyger Peter S
Oregon Hearing Research Center, Oregon Health & Science University, Portland, OR, United States.
National Center for Rehabilitative Auditory Research, Portland VA Medical Center (VHA), Portland, OR, United States.
Front Cell Neurosci. 2017 Oct 9;11:308. doi: 10.3389/fncel.2017.00308. eCollection 2017.
Aminoglycoside antibiotics are used as prophylaxis, or urgent treatment, for many life-threatening bacterial infections, including tuberculosis, sepsis, respiratory infections in cystic fibrosis, complex urinary tract infections and endocarditis. Although aminoglycosides are clinically-essential antibiotics, the mechanisms underlying their selective toxicity to the kidney and inner ear continue to be unraveled despite more than 70 years of investigation. The following mechanisms each contribute to aminoglycoside-induced toxicity after systemic administration: (1) drug trafficking across endothelial and epithelial barrier layers; (2) sensory cell uptake of these drugs; and (3) disruption of intracellular physiological pathways. Specific factors can increase the risk of drug-induced toxicity, including sustained exposure to higher levels of ambient sound, and selected therapeutic agents such as loop diuretics and glycopeptides. Serious bacterial infections (requiring life-saving aminoglycoside treatment) induce systemic inflammatory responses that also potentiate the degree of ototoxicity and permanent hearing loss. We discuss prospective clinical strategies to protect auditory and vestibular function from aminoglycoside ototoxicity, including reduced cochlear or sensory cell uptake of aminoglycosides, and otoprotection by ameliorating intracellular cytotoxicity.
氨基糖苷类抗生素被用作多种危及生命的细菌感染的预防或紧急治疗药物，包括结核病、败血症、囊性纤维化患者的呼吸道感染、复杂性尿路感染和心内膜炎。尽管氨基糖苷类抗生素是临床上必不可少的抗生素，但尽管经过70多年的研究，其对肾脏和内耳选择性毒性的潜在机制仍有待阐明。以下机制均导致全身给药后氨基糖苷类抗生素诱导的毒性：（1）药物穿过内皮和上皮屏障层的转运；（2）这些药物被感觉细胞摄取；（3）细胞内生理途径的破坏。特定因素会增加药物诱导毒性的风险，包括持续暴露于较高水平的环境声音，以及某些治疗药物，如袢利尿剂和糖肽类。严重的细菌感染（需要使用挽救生命的氨基糖苷类抗生素治疗）会引发全身炎症反应，这也会增强耳毒性和永久性听力损失的程度。我们讨论了保护听觉和前庭功能免受氨基糖苷类耳毒性影响的前瞻性临床策略，包括减少氨基糖苷类抗生素在耳蜗或感觉细胞的摄取，以及通过改善细胞内细胞毒性来进行耳保护。
