Pharmacodynamic activity of ertapenem versus genotypically characterized extended-spectrum β-lactamase (ESBL)-, KPC- or NDM-producing Escherichia coli with reduced susceptibility or resistance to ertapenem using an in vitro model.
OBJECTIVE
We assessed the pharmacodynamic activity of ertapenem against Escherichia coli with reduced susceptibility (MIC 0.12-0.5 mg/L), intermediate resistance (MIC 1.0 mg/L) or resistance (MIC ≥ 2 mg/L) to ertapenem using an in vitro model.


METHODS
Fifteen extended-spectrum β-lactamase- or carbapenemase-producing E. coli were studied. The in vitro pharmacodynamic model was inoculated with ∼1 × 10(6) cfu/mL and ertapenem was dosed once daily at 0 and 24 h to simulate free (ƒ) Cmax and t½ obtained after either 1 g or 2 g intravenous once-daily doses in healthy volunteers (1 g: ƒCmax 15 mg/L, t½ 4 h). Sampling was performed over 48 h to assess viable growth and resistance selection.


RESULTS
An ertapenem T> MIC ≥ 75.4% (ertapenem MICs ≤ 0.5 mg/L) resulted in bactericidal (≥ 3 log10 killing) activity against all strains. An ertapenem T>MIC of 61% was bactericidal at 6 and 12 h but regrowth at 24 and 48 h occurred in some strains. An ertapenem T>MIC of 13%-43% was bactericidal at 6 h but regrowth (with MIC increases) occurred. No inhibition of an NDM strain with an ertapenem T>MIC of 0% (ertapenem MIC 256 mg/L) occurred at any timepoint.


CONCLUSIONS
Once-daily dosing with 1 g of ertapenem was bactericidal against ESBL-producing E. coli with ertapenem MICs ≤ 0.5 mg/L and was bactericidal against strains with MICs of 1.0 mg/L, with regrowth in some strains. Ertapenem MICs of 2-8 mg/L resulted in early bactericidal activity followed by regrowth. Once-daily dosing with 2 g of ertapenem was bactericidal against strains with an MIC of 1.0 mg/L, but regrowth occurred in some strains with an ertapenem MIC of 2 mg/L.
Department of Medical Microbiology, Faculty of Medicine, University of Manitoba, 727 McDermot Avenue, Winnipeg, Canada R3E 3P5 Department of Clinical Microbiology, Health Sciences Centre, MS673-Microbiology, 820 Sherbrook Street, Winnipeg, Canada R3A 1R9 Department of Medicine, Health Sciences Centre, 820 Sherbrook Street, Winnipeg, Canada R3A 1R9 ggzhanel@pcs.mb.ca.
George G
GG
Zhanel
Department of Medical Microbiology, Faculty of Medicine, University of Manitoba, 727 McDermot Avenue, Winnipeg, Canada R3E 3P5.
Andrew
A
Denisuik
Department of Medical Microbiology, Faculty of Medicine, University of Manitoba, 727 McDermot Avenue, Winnipeg, Canada R3E 3P5.
Shivangi
S
Vashisht
Department of Medical Microbiology, Faculty of Medicine, University of Manitoba, 727 McDermot Avenue, Winnipeg, Canada R3E 3P5.
Chris
C
Yachison
Department of Medical Microbiology, Faculty of Medicine, University of Manitoba, 727 McDermot Avenue, Winnipeg, Canada R3E 3P5 Department of Clinical Microbiology, Health Sciences Centre, MS673-Microbiology, 820 Sherbrook Street, Winnipeg, Canada R3A 1R9.
Heather J
HJ
Adam
Department of Medical Microbiology, Faculty of Medicine, University of Manitoba, 727 McDermot Avenue, Winnipeg, Canada R3E 3P5 Department of Clinical Microbiology, Health Sciences Centre, MS673-Microbiology, 820 Sherbrook Street, Winnipeg, Canada R3A 1R9.
Daryl J
DJ
Hoban
D000900:Anti-Bacterial Agents / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D000077727:Ertapenem; D004926:Escherichia coli / Q000187:drug effects* / Q000201:enzymology; D006801:Humans; D008826:Microbial Sensitivity Tests; D050296:Microbial Viability / Q000187:drug effects; D018440:beta-Lactam Resistance; D001618:beta-Lactamases / Q000235:genetics / Q000378:metabolism*; D047090:beta-Lactams / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*
D000900:Anti-Bacterial Agents; D047090:beta-Lactams; D001618:beta-Lactamases; D000077727:Ertapenem
E. coli; PD; antimicrobial