title: Comparison of the effects of aztreonam and tigemonam against Escherichia coli and Klebsiella pneumoniae in vitro and in vivo.
abstract: A study was performed to investigate the pharmacodynamics of aztreonam and tigemonam against Escherichia coli and Klebsiella pneumoniae in vitro and in vivo. The in vitro concentration-effect relationships were determined in short-term growth experiments. The in vivo dose-effect relationships were determined in an experimental thigh muscle infection in irradiated mice. In this model, E. coli was injected into one thigh muscle and K. pneumoniae was injected into the other. Throughout these experiments aztreonam was administered subcutaneously and tigemonam was administered orally. For analysis of the antibacterial pharmacodynamics, the following parameters were determined: the maximum effect as a parameter for efficacy, the 50% effective concentration (or dose) as a parameter for potency, and the slope of the concentration-effect relationship. To assess the relationship between the concentration of the antibiotic and the antibacterial effect in vivo, the pharmacokinetics of the two drugs in the plasma of mice were determined as well. The maximum in vitro and in vivo effects of aztreonam and tigemonam against both bacteria did not differ substantially. However, both drugs killed E. coli more effectively than K. pneumoniae, indicating that the maximum in vitro effect of these drugs against E. coli was higher than that against K. pneumoniae. The maximum in vivo effect of both drugs against E. coli was similar to that against K. pneumoniae. Furthermore, in vitro aztreonam was about twice as potent as tigemonam, but in vivo the reverse was the case. These findings were explained by pharmacokinetic differences between subcutaneously administered aztreonam and orally administered tigemonam, because concentrations of tigemonam in plasma remained at microbiologically active concentrations longer than those of aztreonam did.
authors.affiliation: Department of Infectious Diseases, University Hospital, Leiden, The Netherlands.
authors.forename: M L
authors.initials: ML
authors.lastname: van Ogtrop
authors.forename: H
authors.initials: H
authors.lastname: Mattie
authors.forename: H F
authors.initials: HF
authors.lastname: Guiot
authors.forename: E
authors.initials: E
authors.lastname: van Strijen
authors.forename: B R
authors.initials: BR
authors.lastname: Sekh
authors.forename: R
authors.initials: R
authors.lastname: van Furth
mesh_terms: D000818:Animals; D001398:Aztreonam / Q000097:blood / Q000493:pharmacokinetics / Q000627:therapeutic use*; D002478:Cells, Cultured; D002851:Chromatography, High Pressure Liquid; D004305:Dose-Response Relationship, Drug; D004926:Escherichia coli / Q000187:drug effects*; D004927:Escherichia coli Infections / Q000188:drug therapy*; D005260:Female; D007710:Klebsiella Infections / Q000188:drug therapy*; D007711:Klebsiella pneumoniae / Q000187:drug effects*; D051379:Mice; D008826:Microbial Sensitivity Tests; D008997:Monobactams / Q000097:blood / Q000493:pharmacokinetics / Q000627:therapeutic use*
chemical_list: D008997:Monobactams; C052020:tigemonam; D001398:Aztreonam