Pharmacodynamic activity of ertapenem versus multidrug-resistant genotypically characterized extended-spectrum beta-lactamase-producing Escherichia coli using an in vitro model.

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 >= 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) C-max and t(1/2) obtained after a standard 1 g intravenous once-daily dose in healthy volunteers (fC(max), 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 >= 98% (ertapenem MICs <= 0.25 mg/L) resulted in bactericidal (>= 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 similar to 2 h) against MDR ESBL (CTX-M-15)-producing E. coli (ertapenem MICs <= 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.