Background

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.

Objective

The objective of this study was to identify whether the epithelial lining fluid components inhibit amikacin-mediated bacterial killing.

Methods

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.

Results

In the presence of broth alone, there was rapid and extensive (> 6 − log₁₀) 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 − log₁₀) 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.

Conclusions

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.

中文翻译：

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上皮内衬液环境对阿米卡星抗铜绿假单胞菌药效学的影响

背景

尽管阿米卡星的雾化给药可以实现高上皮内衬液浓度，但这并没有转化为临床试验中患者预后的改善。一个可能的原因是上皮内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。

客观的

本研究的目的是确定上皮内衬液成分是否抑制阿米卡星介导的细菌杀伤。

方法

两种阿米卡星敏感（最低抑制浓度为 2 和 8 毫克/升）铜绿假单胞菌分离株在体外暴露于浓度高达 976 毫克/升的阿米卡星，在酸性 pH、粘蛋白和/或表面活性剂存在下作为模拟手段上皮衬里液，肺炎中细菌感染的部位。药效学模型用于描述阿米卡星浓度、细菌杀灭和耐药性出现之间的关联。

结果

在单独存在肉汤的情况下，可以快速和广泛地（> 6 - log ₁₀）杀死细菌，并在阿米卡星浓度 < 976 mg/L 时出现耐药性。相比之下，当暴露于酸性 pH 值和粘蛋白时，细菌杀死的速度和程度会降低 (≤ 5 - log ₁₀ )。对于任一分离株，与单独的肉汤相比，表面活性剂对细菌的杀灭或耐药性的出现没有明显影响。粘蛋白和酸性 pH 值的组合进一步降低了细菌杀灭率，与单独使用粘蛋白或酸性 pH 值相比，在初始暴露后 24 小时发生最大的细菌杀灭作用时间约为 4-8 小时。

结论

我们的研究结果表明，即使在雾化给药后达到的高浓度下，模拟上皮内衬液也会拮抗阿米卡星介导的铜绿假单胞菌杀伤。