Synergistic killing of Multidrug-Resistant Pseudomonas aeruginosa at multiple inocula by colistin combined with doripenem in an in vitro pharmacokinetic/pharmacodynamic model

Bergen, Phillip J., Tsuji, Brian T., Bulitta, Jurgen B., Forrest, Alan, Jacob, Jovan, Sidjabat, Hanna E., Paterson, David L., Nation, Roger L. and Li, Jian (2011) Synergistic killing of Multidrug-Resistant Pseudomonas aeruginosa at multiple inocula by colistin combined with doripenem in an in vitro pharmacokinetic/pharmacodynamic model. Antimicrobial Agents and Chemotherapy, 55 12: 5685-5695. doi:10.1128/AAC.05298-11

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Author Bergen, Phillip J.
Tsuji, Brian T.
Bulitta, Jurgen B.
Forrest, Alan
Jacob, Jovan
Sidjabat, Hanna E.
Paterson, David L.
Nation, Roger L.
Li, Jian
Title Synergistic killing of Multidrug-Resistant Pseudomonas aeruginosa at multiple inocula by colistin combined with doripenem in an in vitro pharmacokinetic/pharmacodynamic model
Formatted title
Synergistic killing of Multidrug-Resistant Pseudomonas aeruginosa at multiple inocula by colistin combined with doripenem in an in vitro pharmacokinetic/pharmacodynamic model
Journal name Antimicrobial Agents and Chemotherapy   Check publisher's open access policy
ISSN 0066-4804
1098-6596
Publication date 2011-09-12
Sub-type Article (original research)
DOI 10.1128/AAC.05298-11
Open Access Status File (Publisher version)
Volume 55
Issue 12
Start page 5685
End page 5695
Total pages 11
Place of publication Washington, DC, United States
Publisher American Society for Microbiology
Collection year 2012
Language eng
Formatted abstract
Combination therapy may be required for multidrug-resistant (MDR) Pseudomonas aeruginosa. The aim of this study was to systematically investigate bacterial killing and emergence of colistin resistance with colistin and doripenem combinations  against MDR P. aeruginosa. Studies were conducted in a one-compartment in vitro pharmacokinetic/pharmacodynamic model for 96 h at two inocula (~106 and ~108 CFU/ml) against a colistin-heteroresistant reference strain (ATCC 27853) and a colistin-resistant MDR clinical isolate (19147 n/m). Four combinations utilizing clinically achievable concentrations were investigated. Microbiological response was examined by log changes and population analysis profiles. Colistin (constant  concentrations of 0.5 or 2 mg/liter) plus doripenem (peaks of 2.5 or 25 mg/liter every 8 h; half-life, 1.5 h) substantially increased bacterial killing against both strains at the low inoculum, while combinations containing colistin at 2 mg/liter increased activity against ATCC 27853 at the high inoculum; only colistin at 0.5 mg/liter plus doripenem at 2.5 mg/liter failed to improve activity against 19147 n/m at the high inoculum.  Combinations were additive or synergistic against ATCC 27853 in 16 and 11 of 20 cases (4 combinations across 5 sample points) at the 106- and 108- CFU/ml inocula, respectively; the corresponding values for 19147 n/m were 16 and 9. Combinations
containing doripenem at 25 mg/liter resulted in eradication of 19147 n/m at the low inoculum and substantial reductions in regrowth (including to below the limit of  detection at ~50 h) at the high inoculum. Emergence of colistin-resistant subpopulations of ATCC 27853 was substantially reduced and delayed with combination therapy. This investigation provides important information for optimization of colistin-doripenem combinations.
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Q-Index Status Confirmed Code
Institutional Status UQ

Document type: Journal Article
Sub-type: Article (original research)
Collections: UQ Centre for Clinical Research Publications
Official 2012 Collection
School of Medicine Publications
 
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Citation counts: TR Web of Science Citation Count  Cited 42 times in Thomson Reuters Web of Science Article | Citations
Scopus Citation Count Cited 46 times in Scopus Article | Citations
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Created: Wed, 19 Oct 2011, 13:02:19 EST by Laurie Beechey on behalf of UQ Centre for Clinical Research