Dataset Information

Impact of the Epithelial Lining Fluid Milieu on Amikacin Pharmacodynamics Against Pseudomonas aeruginosa.

ABSTRACT:

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.

SUBMITTER: Heffernan AJ

PROVIDER: S-EPMC8017437 | biostudies-literature |

REPOSITORIES: biostudies-literature

ACCESS DATA

Similar Datasets

Project description:Relebactam is a novel class A/C β-lactamase inhibitor that restores imipenem in vitro activity against multidrug-resistant and carbapenem-nonsusceptible Pseudomonas aeruginosa Time-kill analyses were performed to evaluate the potential role of imipenem-relebactam in combination with amikacin or colistin against P. aeruginosa Ten clinical P. aeruginosa isolates (9 imipenem nonsusceptible) with imipenem-relebactam MICs ranging from 1/4 to 8/4 μg/ml were included. The isolates had varied susceptibilities to imipenem (1 to 32 μg/ml), amikacin (4 to 128 μg/ml), and colistin (0.5 to 1 μg/ml). Duplicate 24-h time-kill studies were conducted using the average steady-state concentrations (Cssavg) observed after the administration of imipenem-relebactam at 500 mg/250 mg every 6 hours (q6h) alone and in combination with the Cssavg of 25 mg/kg of body weight/day amikacin and 360 mg/day colistin in humans. Imipenem-relebactam alone resulted in 24-h bacterial densities of -2.93 ± 0.38, -1.67 ± 0.29, +0.38 ± 0.96, and +0.15 ± 0.65 log10 CFU/ml at imipenem-relebactam MICs of 1/4, 2/4, 4/4, and 8/4 μg/ml, respectively. No synergy was demonstrated against the single imipenem-susceptible isolate. Against the imipenem-nonsusceptible isolates (n = 9), imipenem-relebactam combined with amikacin resulted in synergy (-2.61 ± 1.50 log10 CFU/ml) against all amikacin-susceptible isolates and in two of three amikacin-intermediate (i.e., MIC, 32 μg/ml) isolates (-2.06 ± 0.19 log10 CFU/ml). Synergy with amikacin was not observed when the amikacin MIC was >32 μg/ml. Imipenem-relebactam combined with colistin demonstrated synergy in eight out of the nine imipenem-resistant isolates (-3.17 ± 1.00 log10 CFU/ml). Against these 10 P. aeruginosa isolates, imipenem-relebactam combined with either amikacin or colistin resulted in synergistic activity against the majority of strains. Further studies evaluating combination therapy with imipenem-relebactam are warranted.