Pharmacodynamics of Aerosolized Fosfomycin and Amikacin against Resistant Clinical Isolates of <i>Pseudomonas aeruginosa</i> and <i>Klebsiella pneumoniae</i> in a Hollow-Fiber Infection Model: Experimental Basis for Combination Therapy



Sime, Fekade Bruck, Johnson, Adam ORCID: 0000-0002-6684-3321, Whalley, Sarah, Santoyo-Castelazo, Anahi, Montgomery, A Bruce, Walters, Kathie Ann, Lipman, Jeffrey, Hope, William W ORCID: 0000-0001-6187-878X and Roberts, Jason A
(2017) Pharmacodynamics of Aerosolized Fosfomycin and Amikacin against Resistant Clinical Isolates of <i>Pseudomonas aeruginosa</i> and <i>Klebsiella pneumoniae</i> in a Hollow-Fiber Infection Model: Experimental Basis for Combination Therapy. ANTIMICROBIAL AGENTS AND CHEMOTHERAPY, 61 (1). e01763-e01716.

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Pharmacodynamics of Aerosolized Fosfomycin and Amikacin against Resistant Clinical Isolates of Pseudomonas aeruginosa and Klebsiella pneumoniae in a Hollow-Fiber Infection Model: Experimental Basis for Combination Therapy.pdf - Published version

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Abstract

There has been a resurgence of interest in aerosolization of antibiotics for treatment of patients with severe pneumonia caused by multidrug-resistant pathogens. A combination formulation of amikacin-fosfomycin is currently undergoing clinical testing although the exposure-response relationships of these drugs have not been fully characterized. The aim of this study was to describe the individual and combined antibacterial effects of simulated epithelial lining fluid exposures of aerosolized amikacin and fosfomycin against resistant clinical isolates of Pseudomonas aeruginosa (MICs of 16 mg/liter and 64 mg/liter) and Klebsiella pneumoniae (MICs of 2 mg/liter and 64 mg/liter) using a dynamic hollow-fiber infection model over 7 days. Targeted peak concentrations of 300 mg/liter amikacin and/or 1,200 mg/liter fosfomycin as a 12-hourly dosing regimens were used. Quantitative cultures were performed to describe changes in concentrations of the total and resistant bacterial populations. The targeted starting inoculum was 10<sup>8</sup> CFU/ml for both strains. We observed that neither amikacin nor fosfomycin monotherapy was bactericidal against P. aeruginosa while both were associated with rapid amplification of resistant P. aeruginosa strains (about 10<sup>8</sup> to 10<sup>9</sup> CFU/ml within 24 to 48 h). For K. pneumoniae, amikacin but not fosfomycin was bactericidal. When both drugs were combined, a rapid killing was observed for P. aeruginosa and K. pneumoniae (6-log kill within 24 h). Furthermore, the combination of amikacin and fosfomycin effectively suppressed growth of resistant strains of P. aeruginosa and K. pneumoniae In conclusion, the combination of amikacin and fosfomycin was effective at maximizing bacterial killing and suppressing emergence of resistance against these clinical isolates.

Item Type: Article
Uncontrolled Keywords: pharmacokinetics, pharmacodynamics, multidrug resistance, nebulized
Depositing User: Symplectic Admin
Date Deposited: 23 Mar 2017 08:06
Last Modified: 13 Feb 2024 15:10
DOI: 10.1128/AAC.01763-16
Related URLs:
URI: https://livrepository.liverpool.ac.uk/id/eprint/3006562