title: Pharmacodynamic activity of ertapenem versus multidrug-resistant genotypically characterized extended-spectrum beta-lactamase-producing Escherichia coli using an in vitro model.
abstract: BACKGROUND
  This study assessed the pharmacodynamic activity of ertapenem against multidrug-resistant (MDR) genotypically characterized extended-spectrum beta-lactamase (ESBL)-producing Escherichia coli using an in vitro model.
  
  
  METHODS
  Six ESBL-producing E. coli with the CTX-M-15 genotype were studied. All six strains were MDR (defined as resistance to third-generation cephalosporins and > or = two other unrelated antimicrobial classes). The in vitro pharmacodynamic model was inoculated with 1 x 10(6) cfu/mL, and ertapenem was dosed once daily at 0 and 24 h to simulate free (f) Cmax and t(1/2) obtained after a standard 1 g intravenous once-daily dose in healthy volunteers (fCmax, 15 mg/L; t(1/2), 4 h). Sampling was performed over 48 h to assess viable growth and resistance selection.
  
  
  RESULTS
  Ertapenem T(>MIC) > or = 98% (ertapenem MICs < or = 0.25 mg/L) resulted in bactericidal (> or = 3 log(10) killing) activity at 6, 12, 24 and 48 h against all strains. Eradication of organisms from the in vitro model (below the level of detection) occurred at 2 h followed by slow regrowth of the majority of the strains (5 of 6) over 12, 24 and 48 h time points. Despite limited regrowth, ertapenem achieved a bactericidal effect against all strains (all time points) over the 48 h study period.
  
  
  CONCLUSIONS
  Ertapenem was rapidly bactericidal (in approximately 2 h) against MDR ESBL (CTX-M-15)-producing E. coli (ertapenem MICs < or = 0.25 mg/L) when simulating free drug after 1 g intravenous once-daily dosing. This bactericidal activity was maintained over the 48 h experimental period with only minor regrowth, which was not associated with MIC increase from baseline.
authors.affiliation: Department of Medical Microbiology, Faculty of Medicine, University of Manitoba, MS673-Microbiology, 820 Sherbrook Street, Winnipeg, Canada R3A 1R9. ggzhanel@pcs.mb.ca
authors.forename: George G
authors.initials: GG
authors.lastname: Zhanel
authors.forename: Patricia
authors.initials: P
authors.lastname: Baudry
authors.forename: Vibhu
authors.initials: V
authors.lastname: Vashisht
authors.forename: Nancy
authors.initials: N
authors.lastname: Laing
authors.forename: Ayman M
authors.initials: AM
authors.lastname: Noreddin
authors.forename: Daryl J
authors.initials: DJ
authors.lastname: Hoban
mesh_terms: D024901:Drug Resistance, Multiple, Bacterial / Q000187:drug effects* / Q000235:genetics; D000077727:Ertapenem; D004926:Escherichia coli / Q000187:drug effects* / Q000201:enzymology* / Q000235:genetics; D005838:Genotype; D006801:Humans; D008954:Models, Biological; D001618:beta-Lactamases / Q000235:genetics* / Q000378:metabolism; D047090:beta-Lactams / Q000494:pharmacology*
chemical_list: D047090:beta-Lactams; D001618:beta-Lactamases; D000077727:Ertapenem