The emergence of multidrug resistant bacteria world wide is a serious problem, and very few new drugs are under development. The selection of resistant bacteria is affected by factors such as mutation rate, biological fitness cost and the rate of fitness compensation. This thesis is focused on how mutation rate affects resistance to fluoroquinolones and on exploring a dosing strategy that might slow resistance development.In a set of urinary tract Escherichia coli isolates MIC values above the breakpoint for the fluoroquinolones norfloxacin and ciprofloxacin carried at least three resistance-associated mutations. In these isolates the number of resistance mutations correlated with the mutation rate. During step-wise selection for decreased susceptibility to fluoroquinolones, the accumulation of mutations in E. coli was associated with an increasing biological cost both in vitro and in vivo…
Contents
INTRODUCTION
Overview
History of infectious diseases
Urinary tract infections
Antibiotics
Classification of Antibiotics
Mode of action
Mechanism of antibiotic resistance
The fluoroquinolones and resistance mechanisms
The target enzymes
FQ resistance mechanisms
The FQ target mutations
Influx and efflux of FQs
Plasmid-mediated FQ resistance
Fluoroquinolone resistance mutations in DNA gyrase and Topo IV and their biological effects
The multidrug-resistant mechanisms
Pharmacokinetics and pharmacodynamics
Pharmacodynamic definitions
PK/PD indices
Effect of biological factors on antibiotic resistance development and persistence of resistance
The biological fitness cost of resistance mutations
Compensation of resistance mutations
Bacterial mutation rate and the mutator genotype
How to measure mutation rate and mutation frequency
Classification of mutators
Transient mutator phenotypes
Mutator effect in bacteria
Mutators in natural and clinical isolates
The emergence of antibiotic resistance
The effect of selection pressures on bacterial population
Mutators, one driving force of antibiotic resistance
Antibiotics, one driving force of mutator development
The Antibiotic resistance surveillance and antibiotic consumption
Prevention of resistance development
PRESENT INVESTIGATION
Summary of papers
Paper I
Paper II
Paper III
Paper IV
Paper V
FUTURE PERSPECTIVES
Summary in Swedish
Acknowledgements
References
Author: Komp Lindgren, Patricia
Source: Uppsala University Library
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