Antimicrobial pharmacodynamics: The gentamicin - Escherichia coli relationship
Kilroy, Carolyn S.
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Permalink
https://hdl.handle.net/2142/22515
Description
Title
Antimicrobial pharmacodynamics: The gentamicin - Escherichia coli relationship
Author(s)
Kilroy, Carolyn S.
Issue Date
1995
Doctoral Committee Chair(s)
Bevill, R.F.
Department of Study
Comparative Biosciences
Discipline
Comparative Biosciences
Degree Granting Institution
University of Illinois at Urbana-Champaign
Degree Name
Ph.D.
Degree Level
Dissertation
Keyword(s)
Biology, Microbiology
Health Sciences, Pharmacology
Language
eng
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.
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