Files in this item



application/pdf9624387.pdf (7MB)Restricted to U of Illinois
(no description provided)PDF


Title:Antimicrobial pharmacodynamics: The gentamicin - Escherichia coli relationship
Author(s):Kilroy, Carolyn S.
Doctoral Committee Chair(s):Bevill, R.F.
Department / Program:Comparative Biosciences
Discipline:Comparative Biosciences
Degree Granting Institution:University of Illinois at Urbana-Champaign
Subject(s):Biology, Microbiology
Health Sciences, Pharmacology
Abstract:The purpose of this thesis was to: (1) explore the in vitro dose-response relationship between gentamicin and Escherichia coli under conditions of constant and declining antibiotic concentrations and (2) to characterize the kinetics of the relationship in an attempt to better predict antimicrobial efficacy. A unique in vitro dynamic culture system was constructed to subject bacteria growing in broth culture to drug concentrations simulating in vivo gentamicin exposure. Changes in viability were monitored as a function of antibiotic concentration and duration of exposure following continuous and IV bolus dose simulations. Significant bacterial killing first occurred at gentamicin concentrations equal to 1/2 the MIC. Exposure to drug concentrations between 1/2 and 2 $\times$ the MIC resulted in a 99.9% loss of viability, followed by resistant regrowth within 4 hours. Resistant bacteria were also identified after single IV bolus dose exposure. Drug resistance was increased up to 8 $\times$ the original MIC and was unstable in antibiotic-free media.
Data from all experiments was analyzed using response surface methodologies and biological modeling techniques. The pharmacodynamics of the gentamicin-E. coli relationship were found to be similar under variable drug exposure conditions by response surface modeling. Duration of drug exposure was considered to be statistically significant, while drug concentration was considered significant only in relation to quadratic concentration-time interactions. Mechanistically, the biologically based pharmacodynamic model suggested that bacterial uptake of gentamicin could be explained by normal physiochemical processes, contrary to hypotheses proposing sophisticated uptake mechanisms. The role of adaptive down-regulation of drug uptake, as a mechanism of acquired resistance, was also explored.
Issue Date:1995
Rights Information:Copyright 1995 Kilroy, Carolyn S.
Date Available in IDEALS:2011-05-07
Identifier in Online Catalog:AAI9624387
OCLC Identifier:(UMI)AAI9624387

This item appears in the following Collection(s)

Item Statistics