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 β-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 × 106 cfu/mL, and ertapenem was dosed once daily at 0 and 24 h to simulate free (f) Cmax and t1/2 obtained after a standard 1 g intravenous once-daily dose in healthy volunteers (fCmax, 15 mg/L; t1/2, 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 log10 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 ∼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.
Zhanel GG, Baudry P, Vashisht V, Laing N, Noreddin AM, Hoban DJ. Pharmacodynamic activity of ertapenem versus multidrug-resistant genotypically characterized extended-spectrum beta-lactamase-producing Escherichia coli using an in vitro model. J Antimicrob Chemother. 2008;61(3):643-6. doi: 10.1093/jac/dkm533