Determination of the pharmacodynamic activity of clinically achievable tigecycline serum concentrations against clinical isolates of Escherichia coli with extended-spectrum beta-lactamases, AmpC beta-lactamases and reduced susceptibility to carbapenems using an in vitro model.
BACKGROUND
Escherichia coli harbouring extended-spectrum beta-lactamases (ESBLs), AmpC beta-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 > or = 0.12 mg/L). The pharmacodynamic model was inoculated with organisms at 1 x 10(6) cfu/mL and tigecycline dosed once every 24 h to simulate the fC(max) (free peak serum concentration) and t(1/2) (serum half-life) obtained after standard dosing of 100 mg intravenously every 24 h (fC(max), 0.15 mg/L; t(1/2), 42 h). Samples were collected over 48 h.


RESULTS
For isolates with a tigecycline fAUC(24)/MIC of 2.0 (tigecycline MIC = 0.5 mg/L), tigecycline demonstrated bacteriostatic activity with < 1 log(10) reduction in bacterial growth compared with the initial inoculum at 12, 24 and 48 h. Against the two isolates for which the tigecycline fAUC(24)/MIC was 4.0 (tigecycline MIC = 0.25 mg/L), tigecycline demonstrated bacteriostatic activity with approximately 1.5 log(10) reduction in bacterial growth compared with the initial inoculum at 12, 24 and 48 h. Against the two isolates for which the tigecycline fAUC(24)/MIC was 8.0 (tigecycline MIC = 0.12 mg/L), tigecycline demonstrated bacteriostatic activity with approximately 2.0 log(10) reduction in bacterial growth compared with the initial inoculum at 12, 24 and 48 h.


CONCLUSIONS
Tigecycline demonstrated approximately 1-2 log(10) killing against E. coli harbouring ESBLs, AmpC beta-lactamases and CRS when simulating clinically achievable serum concentrations, and represents a potential therapy for infections caused by these isolates.
Zhanel
George G
GG
Department of Medical Microbiology, Faculty of Medicine, University of Manitoba, Winnipeg, Manitoba, Canada. ggzhanel@pcs.mb.ca
Baudry
Patricia J
PJ
Tailor
Franil
F
Cox
Lauren
L
Hoban
Daryl J
DJ
Karlowsky
James A
JA
D000900:Anti-Bacterial Agents / Q000493:pharmacokinetics / Q000494:pharmacology*; D015780:Carbapenems / Q000494:pharmacology; D015169:Colony Count, Microbial; D004926:Escherichia coli / Q000187:drug effects* / Q000201:enzymology / Q000302:isolation & purification; D004927:Escherichia coli Infections / Q000382:microbiology; D006801:Humans; D008826:Microbial Sensitivity Tests / Q000379:methods; D050296:Microbial Viability; D008911:Minocycline / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000494:pharmacology; D008962:Models, Theoretical; D044967:Serum / Q000382:microbiology; D000078304:Tigecycline; D018440:beta-Lactam Resistance; D001618:beta-Lactamases / Q000096:biosynthesis*
D000900:Anti-Bacterial Agents; D015780:Carbapenems; D000078304:Tigecycline; D001618:beta-Lactamases; D008911:Minocycline