title: In vitro activity and post-antibiotic effects of colistin in combination with other antimicrobials against colistin-resistant KPC-producing Klebsiella pneumoniae bloodstream isolates.
abstract: OBJECTIVE
  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.
authors.affiliation: Operative Unit of Clinical Microbiology, S. Orsola-Malpighi University Hospital, Bologna, Italy paolo.gaibani@unibo.it.
authors.forename: Paolo
authors.initials: P
authors.lastname: Gaibani
authors.affiliation: Operative Unit of Clinical Microbiology, S. Orsola-Malpighi University Hospital, Bologna, Italy.
authors.forename: Donatella
authors.initials: D
authors.lastname: Lombardo
authors.affiliation: Department of Medical Sciences and Surgery, Operative Unit of Infectious Diseases, S. Orsola-Malpighi University Hospital, Bologna, Italy.
authors.forename: Russell E
authors.initials: RE
authors.lastname: Lewis
authors.affiliation: Operative Unit of Clinical Microbiology, S. Orsola-Malpighi University Hospital, Bologna, Italy.
authors.forename: Marcella
authors.initials: M
authors.lastname: Mercuri
authors.affiliation: Operative Unit of Clinical Microbiology, S. Orsola-Malpighi University Hospital, Bologna, Italy.
authors.forename: Sonia
authors.initials: S
authors.lastname: Bonora
authors.affiliation: Operative Unit of Clinical Microbiology, S. Orsola-Malpighi University Hospital, Bologna, Italy.
authors.forename: Maria Paola
authors.initials: MP
authors.lastname: Landini
authors.affiliation: Operative Unit of Clinical Microbiology, S. Orsola-Malpighi University Hospital, Bologna, Italy.
authors.forename: Simone
authors.initials: S
authors.lastname: Ambretti
mesh_terms: D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D016470:Bacteremia / Q000382:microbiology; D003091:Colistin / Q000494:pharmacology*; D004269:DNA, Bacterial / Q000235:genetics; D024881:Drug Resistance, Bacterial; D004357:Drug Synergism; D005838:Genotype; D006801:Humans; D007710:Klebsiella Infections / Q000382:microbiology; D007711:Klebsiella pneumoniae / Q000187:drug effects* / Q000302:isolation & purification; D008826:Microbial Sensitivity Tests; D008911:Minocycline / Q000031:analogs & derivatives / Q000494:pharmacology; D016133:Polymerase Chain Reaction; D012293:Rifampin / Q000494:pharmacology; D017422:Sequence Analysis, DNA; D000078304:Tigecycline; D001618:beta-Lactamases / Q000378:metabolism
chemical_list: D000900:Anti-Bacterial Agents; D004269:DNA, Bacterial; D000078304:Tigecycline; D001618:beta-Lactamases; D008911:Minocycline; D012293:Rifampin; D003091:Colistin
keywords: K. pneumoniae; PAEs; bacteraemia; colistin resistance; synergy assays