title: 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.
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 108CFU/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 108to 109CFU/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.
authors: Centre for Translational Anti-infective Pharmacodynamics, School of Pharmacy, The University of Queensland, Brisbane, Queensland, Australia.|Burns, Trauma and Critical Care Research Centre, The University of Queensland, Brisbane, Queensland, Australia.|Department of Molecular and Clinical Pharmacology, The University of Liverpool, Liverpool, United Kingdom.
authors: Fekade Bruck
authors: FB
authors: Sime
authors: Department of Molecular and Clinical Pharmacology, The University of Liverpool, Liverpool, United Kingdom.
authors: Adam
authors: A
authors: Johnson
authors: Department of Molecular and Clinical Pharmacology, The University of Liverpool, Liverpool, United Kingdom.
authors: Sarah
authors: S
authors: Whalley
authors: Department of Molecular and Clinical Pharmacology, The University of Liverpool, Liverpool, United Kingdom.
authors: Anahi
authors: A
authors: Santoyo-Castelazo
authors: Cardeas Pharma Corporation, Seattle, Washington, USA.
authors: A Bruce
authors: AB
authors: Montgomery
authors: Cardeas Pharma Corporation, Seattle, Washington, USA.
authors: Kathie Ann
authors: KA
authors: Walters
authors: Burns, Trauma and Critical Care Research Centre, The University of Queensland, Brisbane, Queensland, Australia.
authors: Jeffrey
authors: J
authors: Lipman
authors: Department of Molecular and Clinical Pharmacology, The University of Liverpool, Liverpool, United Kingdom.
authors: William W
authors: WW
authors: Hope
authors: Centre for Translational Anti-infective Pharmacodynamics, School of Pharmacy, The University of Queensland, Brisbane, Queensland, Australia j.roberts2@uq.edu.au.|Burns, Trauma and Critical Care Research Centre, The University of Queensland, Brisbane, Queensland, Australia.|Department of Molecular and Clinical Pharmacology, The University of Liverpool, Liverpool, United Kingdom.
authors: Jason A
authors: JA
authors: Roberts
mesh_terms: D000336:Aerosols; D000583:Amikacin / Q000493:pharmacokinetics / Q000494:pharmacology*; D000900:Anti-Bacterial Agents / Q000493:pharmacokinetics / Q000494:pharmacology*; D015169:Colony Count, Microbial; D004334:Drug Administration Schedule; D024901:Drug Resistance, Multiple, Bacterial; D004357:Drug Synergism; D004359:Drug Therapy, Combination; D005578:Fosfomycin / Q000493:pharmacokinetics / Q000494:pharmacology*; D006801:Humans; D007711:Klebsiella pneumoniae / Q000187:drug effects* / Q000254:growth & development; D008826:Microbial Sensitivity Tests; D008954:Models, Biological; D011550:Pseudomonas aeruginosa / Q000187:drug effects* / Q000254:growth & development; D020545:Respiratory Mucosa / Q000187:drug effects / Q000382:microbiology
chemical_list: D000336:Aerosols; D000900:Anti-Bacterial Agents; D005578:Fosfomycin; D000583:Amikacin
keywords: multidrug resistance; nebulized; pharmacodynamics; pharmacokinetics