title: Activity of tigecycline alone and in combination with colistin and meropenem against Klebsiella pneumoniae carbapenemase (KPC)-producing Enterobacteriaceae strains by time-kill assay.
abstract: Antibiotic combinations including tigecycline have not been studied against Klebsiella pneumoniae carbapenemase (KPC)-producing pathogens. Tigecycline alone and combined with colistin and meropenem was tested against eight genetically unrelated KPC-producing clinical strains of Enterobacteriaceae (four K. pneumoniae, two Escherichia coli, one Enterobacter cloacae and one Serratia marcescens) by time-kill assay. Tigecycline displayed a concentration-independent bacteriostatic activity in seven strains and bactericidal activity in one strain. Colistin showed bactericidal activity at 4× the minimum inhibitory concentration (MIC) in three strains and was bacteriostatic for the remaining strains and concentrations. Meropenem was bactericidal in three strains and bacteriostatic in five strains. The tigecycline+meropenem combination was not bactericidal against the four K. pneumoniae strains and was non-synergistic against all eight strains. Tigecycline+colistin was bactericidal against all strains at most time intervals and concentrations and was also synergistic at 1× and 2× MIC against most strains up to 4-8h and at 4× MIC up to 24 h against all strains. These findings suggest that, at most drug concentrations, tigecycline, colistin and meropenem as single agents do not exhibit efficient bactericidal activity against most of the KPC-producing strains. Tigecycline alone might be a therapeutic option for infections caused by KPC-producers when bacteriostatic activity is adequate or combined with colistin when bactericidal activity is necessary. Additional in vivo tests are warranted to assess better the killing kinetics of tigecycline combinations against KPC-producers.
authors.affiliation: Department of Microbiology, Medical School, University of Thessaly, Larissa, Greece.
authors.forename: Spyros
authors.initials: S
authors.lastname: Pournaras
authors.forename: Georgia
authors.initials: G
authors.lastname: Vrioni
authors.forename: Evangelia
authors.initials: E
authors.lastname: Neou
authors.forename: John
authors.initials: J
authors.lastname: Dendrinos
authors.forename: Evangelia
authors.initials: E
authors.lastname: Dimitroulia
authors.forename: Aggeliki
authors.initials: A
authors.lastname: Poulou
authors.forename: Athanassios
authors.initials: A
authors.lastname: Tsakris
mesh_terms: D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D001426:Bacterial Proteins / Q000378:metabolism*; D003091:Colistin / Q000494:pharmacology*; D004338:Drug Combinations; D024881:Drug Resistance, Bacterial; D016972:Enterobacter cloacae / Q000187:drug effects / Q000201:enzymology; D004755:Enterobacteriaceae / Q000187:drug effects* / Q000201:enzymology; D004756:Enterobacteriaceae Infections / Q000382:microbiology; D004926:Escherichia coli / Q000187:drug effects / Q000201:enzymology; D006801:Humans; D007711:Klebsiella pneumoniae / Q000187:drug effects / Q000201:enzymology; D000077731:Meropenem; D008826:Microbial Sensitivity Tests; D008911:Minocycline / Q000031:analogs & derivatives* / Q000494:pharmacology; D012706:Serratia marcescens / Q000187:drug effects / Q000201:enzymology; D013845:Thienamycins / Q000494:pharmacology*; D000078304:Tigecycline; D001618:beta-Lactamases / Q000378:metabolism*
chemical_list: D000900:Anti-Bacterial Agents; D001426:Bacterial Proteins; D004338:Drug Combinations; D013845:Thienamycins; D000078304:Tigecycline; D001618:beta-Lactamases; C531581:carbapenemase-2, Klebsiella pneumoniae; D000077731:Meropenem; D008911:Minocycline; D003091:Colistin