title: Three Dimensional Checkerboard Synergy Analysis of Colistin, Meropenem, Tigecycline against Multidrug-Resistant Clinical Klebsiella pneumonia Isolates.
abstract: The spread of carbapenem-non-susceptible Klebsiella pneumoniae strains bearing different resistance determinants is a rising problem worldwide. Especially infections with KPC (Klebsiella pneumoniae carbapenemase) - producers are associated with high mortality rates due to limited treatment options. Recent clinical studies of KPC-blood stream infections revealed that colistin-based combination therapy with a carbapenem and/or tigecycline was associated with significantly decreased mortality rates when compared to colistin monotherapy. However, it remains unclear if these observations can be transferred to K. pneumoniae harboring other mechanisms of carbapenem resistance. A three-dimensional synergy analysis was performed to evaluate the benefits of a triple combination with meropenem, tigecycline and colistin against 20 K. pneumoniae isolates harboring different β-lactamases. To examine the mechanism behind the clinically observed synergistic effect, efflux properties and outer membrane porin (Omp) genes (ompK35 and ompK36) were also analyzed. Synergism was found for colistin-based double combinations for strains exhibiting high minimal inhibition concentrations against all of the three antibiotics. Adding a third antibiotic did not result in further increased synergistic effect in these strains. Antagonism did not occur. These results support the idea that colistin-based double combinations might be sufficient and the most effective combination partner for colistin should be chosen according to its MIC.
authors.affiliation: Center for Infectious Diseases and Infection Control, Jena University Hospital, Erlanger Allee 101, D-07747, Jena, Germany.
authors.forename: Claudia
authors.initials: C
authors.lastname: Stein
authors.affiliation: Center for Infectious Diseases and Infection Control, Jena University Hospital, Erlanger Allee 101, D-07747, Jena, Germany.
authors.forename: Oliwia
authors.initials: O
authors.lastname: Makarewicz
authors.affiliation: Institute of Medical Microbiology, Jena University Hospital, Erlanger Allee 101, D-07747, Jena, Germany.
authors.forename: Jürgen A
authors.initials: JA
authors.lastname: Bohnert
authors.affiliation: Nosocomial Pathogens and Antibiotic Resistance, Robert Koch Institute, Burgstrasse 37, D-8855, Wernigerode, Germany.
authors.forename: Yvonne
authors.initials: Y
authors.lastname: Pfeifer
authors.affiliation: Clinical Epidemiology, Integrated Research and Treatment Center, Center for Sepsis Control and Care (CSCC), Jena University Hospital, Erlanger Allee 101, D-07747, Jena, Germany.
authors.forename: Miriam
authors.initials: M
authors.lastname: Kesselmeier
authors.affiliation: Center for Infectious Diseases and Infection Control, Jena University Hospital, Erlanger Allee 101, D-07747, Jena, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Hagel
authors.affiliation: Center for Infectious Diseases and Infection Control, Jena University Hospital, Erlanger Allee 101, D-07747, Jena, Germany.
authors.forename: Mathias W
authors.initials: MW
authors.lastname: Pletz
mesh_terms: D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D001426:Bacterial Proteins / Q000378:metabolism; D003091:Colistin / Q000494:pharmacology*; D024901:Drug Resistance, Multiple, Bacterial / Q000187:drug effects; D004357:Drug Synergism; D015964:Gene Expression Regulation, Bacterial / Q000187:drug effects; D007711:Klebsiella pneumoniae / Q000187:drug effects* / Q000201:enzymology / Q000302:isolation & purification; D000077731:Meropenem; D008826:Microbial Sensitivity Tests; D008911:Minocycline / Q000031:analogs & derivatives* / Q000494:pharmacology; D018272:Porins / Q000378:metabolism; D013845:Thienamycins / Q000494:pharmacology*; D000078304:Tigecycline
chemical_list: D000900:Anti-Bacterial Agents; D001426:Bacterial Proteins; C119261:OmpK35 porin, Klebsiella pneumoniae; C092233:OmpK36 protein, Klebsiella pneumoniae; D018272:Porins; D013845:Thienamycins; D000078304:Tigecycline; D000077731:Meropenem; D008911:Minocycline; D003091:Colistin