JAC Advance Access originally published online on January 31, 2008
Journal of Antimicrobial Chemotherapy 2008 61(3):643-646; doi:10.1093/jac/dkm533
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Original research |
Pharmacodynamic activity of ertapenem versus multidrug-resistant genotypically characterized extended-spectrum β-lactamase-producing Escherichia coli using an in vitro model
1 Department of Medical Microbiology, Faculty of Medicine, University of Manitoba, MS673-Microbiology, 820 Sherbrook Street, Winnipeg, Canada R3A 1R9 2 Department of Clinical Microbiology, Health Sciences Centre, Winnipeg, Canada R3A 1R9 3 Department of Medicine, Health Sciences Centre, Winnipeg, Canada R3A 1R9 4 College of Pharmacy, University of Minnesota, 1110 Kirby Dr, Duluth, 55812 MN, USA
Received 12 October 2007; returned 4 December 2007; revised 2 December 2007; accepted 12 December 2007
* Correspondence address. Microbiology, Health Sciences Centre, MS673—820 Sherbrook Street, Winnipeg, Manitoba, Canada R3A 1R9. Tel: +1-204-787-4902; Fax: +1-204-787-4699; E-mail: ggzhanel{at}pcs.mb.ca
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 x 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.
Keywords: resistance , antimicrobials , ESBLs , E. coli
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