In vitro activity and post-antibiotic effects of colistin in combination with other antimicrobials against colistin-resistant KPC-producing Klebsiella pneumoniae bloodstream isolates

J Antimicrob Chemother. 2014 Jul;69(7):1856-65. doi: 10.1093/jac/dku065. Epub 2014 Mar 19.


Objectives: Combination therapy is recommended for the treatment of KPC-producing Klebsiella pneumoniae (KPC-Kp), but the optimal regimen for colistin-resistant strains is unknown. We compared the synergistic activity and post-antibiotic effect (PAE) of colistin in combination with other antimicrobials against colistin-susceptible and -resistant KPC-Kp bloodstream isolates.

Methods: The genotypes of nine colistin-susceptible and eight colistin-resistant KPC-Kp bloodstream isolates were analysed using PCR and amplicon sequencing. Combinations of colistin, meropenem, tigecycline, rifampicin and teicoplanin were then screened using the Etest, a chequerboard assay and time-kill studies. Synergistic combinations were also analysed with respect to the PAE in time-kill curves and the PAE at clinically achievable concentrations.

Results: Insertional inactivation of the PhoQ/PhoB two-component regulatory system by mgrB-IS5 was identified in 6/8 (75%) colistin-resistant KPC-Kp. Colistin/rifampicin combinations resulted in no interactions [fractional inhibitory concentration (FIC) indices 1.5-2] for colistin-susceptible strains, but were uniformly synergistic (FIC indices 0.1-0.4) against colistin-resistant KPC-Kp. Time-kill kinetic analysis, at clinically achievable fixed concentrations of rifampicin and colistin, confirmed synergy and produced persistent growth inhibition (3 h) of colistin-resistant KPC-Kp strains exposed to colistin/rifampicin or colistin/rifampicin/tigecycline combinations.

Conclusions: Combinations of colistin plus rifampicin, and less frequently tigecycline, exhibited synergistic activity in vitro against colistin-resistant KPC-Kp strains.

Keywords: K. pneumoniae; PAEs; bacteraemia; colistin resistance; synergy assays.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Anti-Bacterial Agents / pharmacology*
  • Bacteremia / microbiology
  • Colistin / pharmacology*
  • DNA, Bacterial / genetics
  • Drug Resistance, Bacterial*
  • Drug Synergism*
  • Genotype
  • Humans
  • Klebsiella Infections / microbiology
  • Klebsiella pneumoniae / drug effects*
  • Klebsiella pneumoniae / isolation & purification
  • Microbial Sensitivity Tests
  • Minocycline / analogs & derivatives
  • Minocycline / pharmacology
  • Polymerase Chain Reaction
  • Rifampin / pharmacology
  • Sequence Analysis, DNA
  • Tigecycline
  • beta-Lactamases / metabolism


  • Anti-Bacterial Agents
  • DNA, Bacterial
  • Tigecycline
  • beta-Lactamases
  • Minocycline
  • Rifampin
  • Colistin