Synergistic Activity of Colistin-Containing Combinations against Colistin-Resistant Enterobacteriaceae.
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Abstract | Resistance to colistin, a polypeptide drug used as an agent of last resort for the treatment of infections caused by multidrug-resistant (MDR) and extensively drug-resistant (XDR) Gram-negative bacteria, including carbapenem-resistant (CRE), severely limits treatment options and may even transform an XDR organism into one that is pan-resistant. We investigated the synergistic activity of colistin in combination with 19 antibiotics against a collection of 20 colistin-resistant isolates, 15 of which were also CRE. All combinations were tested against all strains using an inkjet printer-assisted digital dispensing checkerboard array, and the activities of those that demonstrated synergy by this method were evaluated against a single isolate in a time-kill synergy study. Eighteen of 19 combinations demonstrated synergy against two or more isolates, and the 4 most highly synergistic combinations (colistin combined with linezolid, rifampin, azithromycin, and fusidic acid) were synergistic against ≥90% of strains. Sixteen of 18 combinations (88.9%) that were synergistic in the checkerboard array were also synergistic in a time-kill study. Our findings demonstrate that colistin in combination with a range of antibiotics, particularly protein and RNA synthesis inhibitors, exhibits synergy against colistin-resistant strains, suggesting that colistin may exert a subinhibitory permeabilizing effect on the Gram-negative bacterial outer membrane even in isolates that are resistant to it. These findings suggest that colistin combination therapy may have promise as a treatment approach for patients infected with colistin-resistant XDR Gram-negative pathogens. |
Year of Publication | 2018
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Journal | Antimicrob Agents Chemother
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Volume | 62
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Issue | 10
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Date Published | 2018 10
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ISSN | 1098-6596
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DOI | 10.1128/AAC.00873-18
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PubMed ID | 30061285
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PubMed Central ID | PMC6153801
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Grant list | T32 AI007061 / AI / NIAID NIH HHS / United States
T32 HD055148 / HD / NICHD NIH HHS / United States
K08 AI132716 / AI / NIAID NIH HHS / United States
UM1 AI104681 / AI / NIAID NIH HHS / United States
U19 AI110818 / AI / NIAID NIH HHS / United States
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