Pharmacodynamic evaluation of plasma and epithelial lining fluid exposures of amikacin against Pseudomonas aeruginosa in a dynamic in vitro hollow-fibre infection model

Thumbnail Image
File version

Version of Record (VoR)

Heffernan, Aaron J
Sime, Fekade B
Sarovich, Derek S
Neely, Michael
Guerra-Valero, Yarmarly
Naicker, Saiyuri
Cottrell, Kyra
Harris, Patrick
Andrews, Katherine T
Ellwood, David
Wallis, Steven C
Lipman, Jeffrey
Grimwood, Keith
Roberts, Jason A
Primary Supervisor
Other Supervisors
File type(s)

Given that aminoglycosides, such as amikacin, may be used for multi-drug resistant Pseudomonas aeruginosa infections, optimization of therapy is paramount for improved treatment outcomes. This study aims to investigate the pharmacodynamics of different simulated intravenous amikacin doses on susceptible P. aeruginosa to inform ventilator-associated pneumonia and sepsis treatment choices.A hollow-fibre infection model with two P. aeruginosa isolates (MIC 2 and 8 mg/L) with an initial inoculum ∼108 colony-forming unit/mL was used to test different amikacin dosing regimens. Three regimens (15, 25 and 50 mg/kg) simulating a blood exposure and a 30 mg/kg regimen simulating the epithelial lining fluid (ELF) for potential respiratory tract infection were tested. Data were described using a semi-mechanistic pharmacokinetic/pharmacodynamic (PK/PD) model. Whole genome sequencing was used to identify mutations associated with resistance emergence.While bacterial density was reduced by >6-logs within the first 12 h in simulated blood exposures, following this initial bacterial kill, there was amplification of a resistant sub-population with ribosomal mutations that were likely mediating amikacin resistance. No appreciable bacterial killing occurred with subsequent doses. There was less (<5-log) bacterial killing in the simulated ELF exposure for either isolate tested. Simulation studies suggest that a dose of 30 and 50 mg/kg may provide maximal bacterial killing for bloodstream and VAP infections respectively.Our results suggest that amikacin efficacy may be improved with the use of high dose therapy to rapidly eliminate susceptible bacteria. Subsequent doses may have reduced efficacy given the rapid amplification of less-susceptible bacterial subpopulations with amikacin monotherapy.

Journal Title

Antimicrobial Agents and Chemotherapy

Conference Title
Book Title
Thesis Type
Degree Program
Publisher link
Patent number
Grant identifier(s)
Rights Statement
Rights Statement

© 2020 American Society for Microbiology. This is the author-manuscript version of this paper. Reproduced in accordance with the copyright policy of the publisher. Please refer to the journal's website for access to the definitive, published version.

Item Access Status
Access the data
Related item(s)


Medical microbiology

Pharmacology and pharmaceutical sciences

Persistent link to this record

Heffernan, AJ; Sime, FB; Sarovich, DS; Neely, M; Guerra-Valero, Y; Naicker, S; Cottrell, K; Harris, P; Andrews, KT; Ellwood, D; Wallis, SC; Lipman, J; Grimwood, K; Roberts, JA, Pharmacodynamic evaluation of plasma and epithelial lining fluid exposures of amikacin against Pseudomonas aeruginosa in a dynamic in vitro hollow-fibre infection model., Antimicrob Agents Chemother, 2020