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JAC Advance Access originally published online on July 29, 2009
Journal of Antimicrobial Chemotherapy 2009 64(4):824-828; doi:10.1093/jac/dkp254
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© The Author 2009. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For Permissions, please e-mail: journals.permissions@oxfordjournals.org

Original research

Determination of the pharmacodynamic activity of clinically achievable tigecycline serum concentrations against clinical isolates of Escherichia coli with extended-spectrum β-lactamases, AmpC β-lactamases and reduced susceptibility to carbapenems using an in vitro model

George G. Zhanel1,2,3,*, Patricia J. Baudry1, Franil Tailor1, Lauren Cox1, Daryl J. Hoban1,2 and James A. Karlowsky1,2

1 Department of Medical Microbiology, Faculty of Medicine, University of Manitoba, Winnipeg, Manitoba, Canada 2 Department of Clinical Microbiology, MS673-Microbiology, Health Sciences Centre, 820 Sherbrook Street, Winnipeg, Manitoba R3A 1R9, Canada 3 Department of Medicine, MS673-Microbiology, Health Sciences Centre, 820 Sherbrook Street, Winnipeg, Manitoba R3A 1R9, Canada

Received 7 May 2009; returned 22 June 2009; revised 25 June 2009; accepted 26 June 2009

* Corresponding author. Microbiology, Health Sciences Centre, MS673, 820 Sherbrook Street, Winnipeg, Manitoba R3A 1R9, Canada. Tel: +1-204/787-4902; Fax: +1-204/787-4699; E-mail: ggzhanel{at}pcs.mb.ca

Background: Escherichia coli harbouring extended-spectrum β-lactamases (ESBLs), AmpC β-lactamases and reduced susceptibility to carbapenems (CRS) are increasing worldwide. This study assessed the in vitro pharmacodynamic activity of tigecycline against E. coli with ESBLs, AmpCs and CRS.

Methods: Nine E. coli isolates were studied, including three ESBL-producing isolates, three AmpC-producing isolates and three isolates demonstrating CRS (ertapenem MIC ≥ 0.12 mg/L). The pharmacodynamic model was inoculated with organisms at 1 x 106 cfu/mL and tigecycline dosed once every 24 h to simulate the fCmax (free peak serum concentration) and t1/2 (serum half-life) obtained after standard dosing of 100 mg intravenously every 24 h (fCmax, 0.15 mg/L; t1/2, 42 h). Samples were collected over 48 h.

Results: For isolates with a tigecycline fAUC24/MIC of 2.0 (tigecycline MIC = 0.5 mg/L), tigecycline demonstrated bacteriostatic activity with <1 log10 reduction in bacterial growth compared with the initial inoculum at 12, 24 and 48 h. Against the two isolates for which the tigecycline fAUC24/MIC was 4.0 (tigecycline MIC = 0.25 mg/L), tigecycline demonstrated bacteriostatic activity with ~1.5 log10 reduction in bacterial growth compared with the initial inoculum at 12, 24 and 48 h. Against the two isolates for which the tigecycline fAUC24/MIC was 8.0 (tigecycline MIC = 0.12 mg/L), tigecycline demonstrated bacteriostatic activity with ~2.0 log10 reduction in bacterial growth compared with the initial inoculum at 12, 24 and 48 h.

Conclusions: Tigecycline demonstrated ~1–2 log10 killing against E. coli harbouring ESBLs, AmpC β-lactamases and CRS when simulating clinically achievable serum concentrations, and represents a potential therapy for infections caused by these isolates.

Keywords: bacterial killing , bactericidal , inhibition


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