Evaluation of double- and triple-antibiotic combinations for VIM- and NDM-producing Klebsiella pneumoniae by in vitro time-kill experiments

Antimicrob Agents Chemother. 2014;58(3):1757-62. doi: 10.1128/AAC.00741-13. Epub 2014 Jan 6.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aminoglycosides / administration & dosage
  • Aminoglycosides / pharmacology
  • Anti-Bacterial Agents / administration & dosage
  • Anti-Bacterial Agents / pharmacology*
  • Aztreonam / administration & dosage
  • Aztreonam / pharmacology
  • Ciprofloxacin / administration & dosage
  • Ciprofloxacin / pharmacology
  • Colistin / administration & dosage
  • Colistin / pharmacology
  • Daptomycin / administration & dosage
  • Daptomycin / pharmacology
  • Drug Resistance, Multiple, Bacterial
  • Drug Synergism
  • Fosfomycin / administration & dosage
  • Fosfomycin / pharmacology
  • In Vitro Techniques
  • Klebsiella pneumoniae / drug effects*
  • Lipoglycopeptides
  • Meropenem
  • Microbial Sensitivity Tests
  • Minocycline / administration & dosage
  • Minocycline / analogs & derivatives
  • Minocycline / pharmacology
  • Rifampin / administration & dosage
  • Rifampin / pharmacology
  • Thienamycins / administration & dosage
  • Thienamycins / pharmacology
  • Tigecycline
  • Vancomycin / administration & dosage
  • Vancomycin / pharmacology
  • beta-Lactamases / metabolism

Substances

  • Aminoglycosides
  • Anti-Bacterial Agents
  • Lipoglycopeptides
  • Thienamycins
  • Fosfomycin
  • Ciprofloxacin
  • Vancomycin
  • Tigecycline
  • beta-Lactamases
  • Meropenem
  • Minocycline
  • Aztreonam
  • Daptomycin
  • Rifampin
  • telavancin
  • Colistin