School of Medicine, Griffith University, Gold Coast, QLD, Australia.
Centre for Translational Anti-infective Pharmacodynamics, School of Pharmacy, The University of Queensland, Cornwall St, Woolloongabba, QLD, 4102, Australia.
Drugs R D. 2021 Jun;21(2):203-215. doi: 10.1007/s40268-021-00344-5. Epub 2021 Apr 2.
Even though nebulised administration of amikacin can achieve high epithelial lining fluid concentrations, this has not translated into improved patient outcomes in clinical trials. One possible reason is that the cellular and chemical composition of the epithelial lining fluid may inhibit amikacin-mediated bacterial killing.
The objective of this study was to identify whether the epithelial lining fluid components inhibit amikacin-mediated bacterial killing.
Two amikacin-susceptible (minimum inhibitory concentrations of 2 and 8 mg/L) Pseudomonas aeruginosa isolates were exposed in vitro to amikacin concentrations up to 976 mg/L in the presence of an acidic pH, mucin and/or surfactant as a means of simulating the epithelial lining fluid, the site of bacterial infection in pneumonia. Pharmacodynamic modelling was used to describe associations between amikacin concentrations, bacterial killing and emergence of resistance.
In the presence of broth alone, there was rapid and extensive (> 6 - log) bacterial killing, with emergence of resistance identified in amikacin concentrations < 976 mg/L. In contrast, the rate and extent of bacterial killing was reduced (≤ 5 - log) when exposed to an acidic pH and mucin. Surfactant did not appreciably impact the bacterial killing or resistance emergence when compared with broth alone for either isolate. The combination of mucin and an acidic pH further reduced the rate of bacterial killing, with the maximal bacterial killing occurring 24 h following initial exposure compared with approximately 4-8 h for either mucin or an acidic pH alone.
Our findings indicate that simulating the epithelial lining fluid antagonises amikacin-mediated killing of P. aeruginosa, even at the high concentrations achieved following nebulised administration.
尽管雾化给予阿米卡星可以使上皮衬液中达到高浓度，但这并未在临床试验中转化为改善患者结局。一个可能的原因是上皮衬液的细胞和化学成分可能会抑制阿米卡星介导的细菌杀伤。
本研究旨在确定上皮衬液成分是否会抑制阿米卡星介导的细菌杀伤。
体外将 2 株对阿米卡星敏感的（最低抑菌浓度为 2 和 8 mg/L）铜绿假单胞菌分离株暴露于高达 976 mg/L 的阿米卡星浓度下，同时存在酸性 pH、黏蛋白和/或表面活性剂，以模拟肺炎中细菌感染部位的上皮衬液。药效动力学模型用于描述阿米卡星浓度、细菌杀伤和耐药性出现之间的关联。
在单独存在肉汤的情况下，存在快速且广泛的 (>6-log) 细菌杀伤，在阿米卡星浓度 <976 mg/L 时出现耐药性。相比之下，当暴露于酸性 pH 和黏蛋白时，细菌杀伤的速度和程度降低（≤5-log）。与单独使用肉汤相比，对于两种分离株，表面活性剂对细菌杀伤或耐药性出现均无明显影响。与单独使用黏蛋白或酸性 pH 相比，黏蛋白和酸性 pH 的组合进一步降低了细菌杀伤的速度，最大细菌杀伤发生在初始暴露后 24 小时，而不是单独使用黏蛋白或酸性 pH 时的大约 4-8 小时。
我们的研究结果表明，模拟上皮衬液拮抗了阿米卡星对铜绿假单胞菌的杀伤作用，即使在雾化给予后达到的高浓度下也是如此。
