title: Evaluation of double- and triple-antibiotic combinations for VIM- and NDM-producing Klebsiella pneumoniae by in vitro time-kill experiments.
abstract: Combination therapy is recommended for infections with carbapenemase-producing Klebsiella pneumoniae. However, limited data exist on which antibiotic combinations are the most effective. The aim of this study was to find effective antibiotic combinations against metallo-beta-lactamase-producing K. pneumoniae (MBL-KP). Two VIM- and two NDM-producing K. pneumoniae strains, all susceptible to colistin, were exposed to antibiotics at clinically relevant static concentrations during 24-h time-kill experiments. Double- and triple-antibiotic combinations of aztreonam, ciprofloxacin, colistin, daptomycin, fosfomycin, meropenem, rifampin, telavancin, tigecycline, and vancomycin were used. Synergy was defined as a ≥2 log10 decrease in CFU/ml between the combination and its most active drug after 24 h, and bactericidal effect was defined as a ≥3 log10 decrease in CFU/ml after 24 h compared with the starting inoculum. Synergistic or bactericidal activity was demonstrated for aztreonam, fosfomycin, meropenem, and rifampin in double-antibiotic combinations with colistin and also for aztreonam, fosfomycin, and rifampin in triple-antibiotic combinations with meropenem and colistin. Overall, the combination of rifampin-meropenem-colistin was the most effective regimen, demonstrating synergistic and bactericidal effects against all four strains. Meropenem-colistin, meropenem-fosfomycin, and tigecycline-colistin combinations were not bactericidal against the strains used. The findings of this and other studies indicate that there is great potential of antibiotic combinations against carbapenemase-producing K. pneumoniae. However, our results deviate to some extent from those of previous studies, which might be because most studies to date have included KPC-producing rather than MBL-producing strains. More studies addressing MBL-KP are needed.
authors.affiliation: Department of Medical Sciences, Section of Infectious Diseases, Uppsala University, Uppsala, Sweden.
authors.forename: T
authors.initials: T
authors.lastname: Tängdén
authors.forename: R A
authors.initials: RA
authors.lastname: Hickman
authors.forename: P
authors.initials: P
authors.lastname: Forsberg
authors.forename: P
authors.initials: P
authors.lastname: Lagerbäck
authors.forename: C G
authors.initials: CG
authors.lastname: Giske
authors.forename: O
authors.initials: O
authors.lastname: Cars
mesh_terms: D000617:Aminoglycosides / Q000008:administration & dosage / Q000494:pharmacology; D000900:Anti-Bacterial Agents / Q000008:administration & dosage / Q000494:pharmacology*; D001398:Aztreonam / Q000008:administration & dosage / Q000494:pharmacology; D002939:Ciprofloxacin / Q000008:administration & dosage / Q000494:pharmacology; D003091:Colistin / Q000008:administration & dosage / Q000494:pharmacology; D017576:Daptomycin / Q000008:administration & dosage / Q000494:pharmacology; D024901:Drug Resistance, Multiple, Bacterial; D004357:Drug Synergism; D005578:Fosfomycin / Q000008:administration & dosage / Q000494:pharmacology; D066298:In Vitro Techniques; D007711:Klebsiella pneumoniae / Q000187:drug effects*; D000077427:Lipoglycopeptides; D000077731:Meropenem; D008826:Microbial Sensitivity Tests; D008911:Minocycline / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000494:pharmacology; D012293:Rifampin / Q000008:administration & dosage / Q000494:pharmacology; D013845:Thienamycins / Q000008:administration & dosage / Q000494:pharmacology; D000078304:Tigecycline; D014640:Vancomycin / Q000008:administration & dosage / Q000494:pharmacology; D001618:beta-Lactamases / Q000378:metabolism
chemical_list: D000617:Aminoglycosides; D000900:Anti-Bacterial Agents; D000077427:Lipoglycopeptides; D013845:Thienamycins; D005578:Fosfomycin; D002939:Ciprofloxacin; D014640:Vancomycin; D000078304:Tigecycline; D001618:beta-Lactamases; D000077731:Meropenem; D008911:Minocycline; D001398:Aztreonam; D017576:Daptomycin; D012293:Rifampin; C487637:telavancin; D003091:Colistin