title: Evaluation of antibacterial activities of colistin, rifampicin and meropenem combinations against NDM-1-producing Klebsiella pneumoniae in 24 h in vitro time-kill experiments.
abstract: To investigate the activity of colistin alone or in double and triple combination with rifampicin and meropenem against NDM-1-producing Klebsiella pneumoniae.
  
  
  
  Eight isolates of NDM-1-producing K. pneumoniae were exposed to clinically relevant antibiotic concentrations in 24 h time-kill experiments. Three colistin concentrations were used for two of the strains. Resistance development was assessed with population analysis and sequencing of the mgrB and pmrB genes.
  
  
  
  Initial killing was achieved with colistin alone, but with considerable regrowth at 24 h. Combinations including colistin and rifampicin were bacteriostatic or bactericidal against all strains. Colistin plus meropenem was bactericidal against one strain, but, overall, meropenem showed little additive effects. Higher concentrations of colistin did not enhance antibacterial activity. Resistant populations and deletion or mutations in the mgrB and pmrB genes were frequently detected in endpoint samples after exposure to colistin alone.
  
  
  
  Based on the results of this and previous studies, the combination of colistin and rifampicin seems promising and should be further explored in vivo and considered for clinical evaluation. Meropenem seems less useful in the treatment of infections caused by high-level carbapenem-resistant NDM-1-producing K. pneumoniae. Higher colistin concentrations did not result in significantly better activity, suggesting that combination therapy might be superior to monotherapy also when colistin is prescribed using high-dose regimens in accordance with current recommendations.
authors.affiliation: Department of Medical Sciences, Section of Infectious Diseases, Uppsala University, Uppsala, Sweden.
authors.forename: P
authors.initials: P
authors.lastname: Lagerbäck
authors.affiliation: Department of Medical Sciences, Section of Infectious Diseases, Uppsala University, Uppsala, Sweden.
authors.forename: W W T
authors.initials: WW
authors.lastname: Khine
authors.affiliation: Division of Clinical Microbiology, Department of Laboratory Medicine, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden.
authors.forename: C G
authors.initials: CG
authors.lastname: Giske
authors.affiliation: Department of Medical Sciences, Section of Infectious Diseases, Uppsala University, Uppsala, Sweden thomas.tangden@medsci.uu.se.
authors.forename: T
authors.initials: T
authors.lastname: Tängdén
mesh_terms: D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D003091:Colistin / Q000494:pharmacology*; D004347:Drug Interactions; D024881:Drug Resistance, Bacterial; D005798:Genes, Bacterial; D006801:Humans; D007711:Klebsiella pneumoniae / Q000187:drug effects* / Q000201:enzymology / Q000235:genetics; D000077731:Meropenem; D008826:Microbial Sensitivity Tests; D050296:Microbial Viability / Q000187:drug effects; D012293:Rifampin / Q000494:pharmacology*; D017422:Sequence Analysis, DNA; D013845:Thienamycins / Q000494:pharmacology*; D001618:beta-Lactamases / Q000235:genetics / Q000378:metabolism*
chemical_list: D000900:Anti-Bacterial Agents; D013845:Thienamycins; D001618:beta-Lactamases; C552864:beta-lactamase NDM-1; D000077731:Meropenem; D012293:Rifampin; D003091:Colistin