Journal article
Pharmacodynamic evaluation of plasma and epithelial lining fluid exposures of amikacin against Pseudomonas aeruginosa in a dynamic in vitro hollow-fibre infection model
Antimicrobial Agents and Chemotherapy, Vol.64(9), pp.1-13
2020
PMCID: PMC7449155
PMID: 32660986
Abstract
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.
Details
- Title
- Pharmacodynamic evaluation of plasma and epithelial lining fluid exposures of amikacin against Pseudomonas aeruginosa in a dynamic in vitro hollow-fibre infection model
- Authors
- Aaron J Heffernan (Author) - Griffith UniversityFekade B Sime (Author) - The University of QueenslandDerek Sarovich (Author) - University of the Sunshine Coast, Queensland, GeneCology Research Centre - LegacyMichael Neely (Author) - University of Southern CaliforniaYarmarly Guerra-Valero (Author) - The University of QueenslandSaiyuri Naicker (Author) - The University of QueenslandKyra Cottrell (Author) - The University of QueenslandPatrick Harris (Author) - The University of QueenslandKatherine T Andrews (Author) - Griffith UniversityDavid Ellwood (Author) - Griffith UniversitySteven C Wallis (Author) - The University of QueenslandJeffrey Lipman (Author) - The University of QueenslandKeith Grimwood (Author) - Griffith UniversityJason A Roberts (Author) - The University of Queensland
- Publication details
- Antimicrobial Agents and Chemotherapy, Vol.64(9), pp.1-13
- Publisher
- American Society of Microbiology
- Date published
- 2020
- DOI
- 10.1128/AAC.00879-20
- ISSN
- 1098-6596
- PMID
- 32660986; PMC7449155
- Organisation Unit
- University of the Sunshine Coast, Queensland; Academic Support Unit; Centre for Bioinnovation
- Language
- English
- Record Identifier
- 99468007702621
- Output Type
- Journal article
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- Microbiology
- Pharmacology & Pharmacy
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