title: Assessment of antimicrobial combinations for Klebsiella pneumoniae carbapenemase-producing K. pneumoniae.
abstract: BACKGROUND
  The prevalence of bla(KPC) among gram-negative bacteria continues to increase worldwide. Limited treatment options exist for this multidrug-resistant phenotype, often necessitating combination therapy. We investigated the in vitro and in vivo efficacy of multiple antimicrobial combinations.
  
  
  METHODS
  Two clinical strains of Klebsiella pneumoniae carbapenemase (KPC)-producing K. pneumoniae were studied. The killing activities of six 2-agent combinations of amikacin, doripenem, levofloxacin, and rifampin were quantitatively assessed using a validated mathematical model. Combination time-kill studies were conducted using clinically relevant concentrations; observed bacterial burdens were modeled using 3-dimensional response surfaces. Selected combinations were further validated in a neutropenic murine pneumonia model, using human-like dosing exposures.
  
  
  RESULTS
  The most enhanced killing effect in time-kill studies was seen with amikacin plus doripenem. Compared with placebo controls, this combination resulted in significant reduction of the bacterial burden in tissue at 24 hours, along with prolonged animal survival. In contrast, amikacin plus levofloxacin was found to be antagonistic in time-kill studies, showing inferior animal survival, as predicted.
  
  
  CONCLUSIONS
  Our modeling approach appeared to be robust in assessing the effectiveness of various combinations for KPC-producing isolates. Amikacin plus doripenem was the most effective combination in both in vitro and in vivo infection models. Empirical selection of combinations against KPCs may result in antagonism and should be avoided.
authors.affiliation: University of Houston, Texas, USA.
authors.forename: Elizabeth B
authors.initials: EB
authors.lastname: Hirsch
authors.forename: Beining
authors.initials: B
authors.lastname: Guo
authors.forename: Kai-Tai
authors.initials: KT
authors.lastname: Chang
authors.forename: Henry
authors.initials: H
authors.lastname: Cao
authors.forename: Kimberly R
authors.initials: KR
authors.lastname: Ledesma
authors.forename: Manisha
authors.initials: M
authors.lastname: Singh
authors.forename: Vincent H
authors.initials: VH
authors.lastname: Tam
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000008:administration & dosage* / Q000494:pharmacology; D058491:Bacterial Load; D001426:Bacterial Proteins / Q000378:metabolism*; D004195:Disease Models, Animal; D004359:Drug Therapy, Combination / Q000379:methods; D005260:Female; D006801:Humans; D007710:Klebsiella Infections / Q000188:drug therapy* / Q000382:microbiology*; D007711:Klebsiella pneumoniae / Q000187:drug effects* / Q000201:enzymology* / Q000302:isolation & purification; D008168:Lung / Q000382:microbiology; D051379:Mice; D008826:Microbial Sensitivity Tests; D050296:Microbial Viability / Q000187:drug effects*; D018410:Pneumonia, Bacterial / Q000188:drug therapy / Q000382:microbiology; D016896:Treatment Outcome; D001618:beta-Lactamases / Q000378:metabolism*
chemical_list: D000900:Anti-Bacterial Agents; D001426:Bacterial Proteins; D001618:beta-Lactamases; C063912:carbapenemase