In vitro synergy and postantibiotic effect of colistin combinations with meropenem and vancomycin against Enterobacteriaceae with multiple carbapenem resistance mechanisms

J Infect Chemother. 2018 Dec;24(12):1016-1019. doi: 10.1016/j.jiac.2018.06.001. Epub 2018 Jul 11.


Aim: The aim of the study was to determine in vitro synergy and postantibiotic effect of colistin alone and combined with meropenem or vancomycin against Enterobacteriaceae producing multiple carbapenemases; combinations of two metallo-β-lactamases (MBL) or MBL with OXA-48. Colistin-resistant strain positive for OXA-48 was also included in the study.

Methods: The antibiotic susceptibility was tested by broth microdilution method. Synergy was tested by chequerboard, time-kill and 2-well method. PAE was determined by viable counting.

Results: The chequerboard analysis revealed synergy for colistin combination with meropenem in all isolates with FICI values ranging from 0.12 to 0.24. FICI values for combinations with vancomycin were below 0.5 indicating synergy in two out of four isolates. K. pneumoniae 609815 positive for OXA-48 and colistin resistant showed the most pronounced and consistent synergy effect with meropenem in both chequerboard and time-kill method. Synergy effect in time-kill curves, was observed for K pneumoniae 145846 with two MBLs and colistin resistant K. pneumoniae 609815 positive for OXA-48, with both combinations including meropenem and vancomycin. Colistin alone exhibited short postantibiotic effect (PAE) against all tested isolates. Meropenem markedly prolonged the PAE in two isolates in contrast to vancomycin which did not demonstrate significant effect on the duration of PAE.

Conclusions: The synergy effect and the duration of PAE was strain and antibiotic dependent but not related to the resistance gene content.

Keywords: Antibiotic synergy; Carbapenem resistance; Colistin; Meropenem; Postantibiotic effect; Vancomycin.

MeSH terms

  • Anti-Bacterial Agents / pharmacology
  • Colistin / pharmacology*
  • Drug Resistance, Multiple, Bacterial / drug effects*
  • Drug Synergism
  • Enterobacter cloacae / drug effects*
  • Enterobacter cloacae / enzymology
  • Klebsiella pneumoniae / drug effects*
  • Klebsiella pneumoniae / enzymology
  • Meropenem / pharmacology*
  • Microbial Sensitivity Tests
  • Vancomycin / pharmacology*
  • beta-Lactam Resistance / drug effects
  • beta-Lactamases / metabolism


  • Anti-Bacterial Agents
  • Vancomycin
  • beta-Lactamases
  • Meropenem
  • Colistin