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

Objectives: 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 beta-lactamase- or carbapenemase-producing E. coli were studied. The in vitro pharmacodynamic model was inoculated with similar to 1x10(6) cfu/mL and ertapenem was dosed once daily at 0 and 24 h to simulate free (f) C-max and t(1/2) obtained after either 1 g or 2 g intravenous once-daily doses in healthy volunteers (1 g: fC(max) 15 mg/L, t(1/2) 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 log(10) 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.