Synergistic Activity of Colistin-Containing Combinations against Colistin-Resistant Enterobacteriaceae

Antimicrob Agents Chemother. 2018 Sep 24;62(10):e00873-18. doi: 10.1128/AAC.00873-18. Print 2018 Oct.


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 Enterobacteriaceae (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 Enterobacteriaceae 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.

Keywords: CRE; Enterobacteriaceae; MCR-1; NDM-1; carbapenem-resistant Enterobacteriaceae; checkerboard; colistin; synergy; time-kill curves.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Anti-Bacterial Agents / pharmacology*
  • Azithromycin / pharmacology
  • Colistin / pharmacology*
  • Drug Resistance, Multiple, Bacterial
  • Drug Synergism
  • Enterobacteriaceae / drug effects*
  • Fusidic Acid / pharmacology
  • Linezolid / pharmacology
  • Microbial Sensitivity Tests
  • Rifampin / pharmacology


  • Anti-Bacterial Agents
  • Fusidic Acid
  • Azithromycin
  • Linezolid
  • Rifampin
  • Colistin