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I the Mutant-Prevention Concentration (MPC)

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I the Mutant-Prevention Concentration (MPC) The Mutant-Prevention Concentration (MPC): Ideas for restricting the development of fluoroquinolone resistance A Thesis Submitted to the College of Graduate Studies and Research in partial fulfillment of the requirements for the Doctoral Degree of Science in the Department of Microbiology and Immunology University of Saskatchewan Saskatoon By Glen T. Hansen Keywords: Antimicrobial resistance, Fluoroquinolone, Mutant-prevention concentration, Pseudomonas aeruginosa, Streptococus pneumoniae, © Copyright Glen Hansen, March, 2005. All rights reserved i PERMISSION TO USE In presenting this thesis in partial fulfillment of the requirements for a postgraduate degree from the University of Saskatchewan, I agree that the Libraries of the University may make it freely available for inspection. I further agree that permission to copy this thesis in any way, in whole or in part, for scholarly purposes only may be granted by the professor or professors who supervised my thesis work or, in their absence, by the Head of the Department of Microbiology and Immunology or the Dean of the College of Graduate Studies and Research. It is understood that any copying or publication or use of this thesis or parts thereof for financial gain shall not be allowed without written permission. It is a also understood that due recognition shall be given to me and to the University of Saskatchewan in any scholarly use which may be made of any materials in my thesis. All requests for permission to copy or to make other use of material in this thesis in whole or part should be addressed to: Head of the Department of Microbiology and Immunology University of Saskatchewan Saskatoon, Saskatchewan S7N 5E5 ii ABSTRACT The mutant-prevention concentration (MPC) is a novel susceptibility measurement defined by a concentration threshold that would require cells to contain two concurrent resistance mutations for growth. Pneuococcal pneumonia, infections caused by Pseudomonas aeruginosa, and urinary tract infections caused by Gram- negative bacilli represent three distinct clinical situations for which fluoroquinolone- resistance occurs. MPC results were defined and measured for fluoroquinolones against clinical isolates of Citrobacter freundii, Enterobacter cloacae, Escherichia. coli, Klebsiella pneumoniae, P. aeruginosa, and Streptococus pneumoniae. Against clinical isolates of S. pneumoniae, MPC results for six fluoroquinolones were measured. Based on their potential for restricting the selection of resistant mutants, the six fluoroquinolones, in descending order, were found to be gemifloxacin > moxifloxacin > trovafloxacin > gatifloxacin > grepafloxacin > levofloxacin. For several compounds, 90% of clinical isolates that lacked a known resistance mutation had a MPC value that was close to or below the serum levels that could be attained with a dosing regimen recommended by the manufacturers. These data identify gemifloxacin, moxifloxacin and gatifloxacin as good candidates for determining whether MPC can be used as a guide for choosing and eventually administering fluoroquinolones to significantly reduce the development of fluoroquinolone –resistant S. pneumoniae. MPC90 results for 155 clinical isolates of P. aeruginosa against ciprofloxacin and levofloxacin were 4 and 16 μg/ml, respectively. Serum drug concentrations reported iii previously for standard doses were above MPC90 for 5.5 hr for ciprofloxacin and 0 hr for levofloxacin. These data suggest that superior clinical performance of ciprofloxacin correlates with activity against resistant mutant subpopulations measured in vitro. MPC results were compared with minimum inhibitory concentrations (MIC) measurements preformed by agar dilution, and microbroth dilution and minimal inhibitory concentrations (MBC) for 100 clinical isolates of C. freundii (n=20), E. cloacae (n=20), E. coli (n=20), K. pneumoniae (n=20), and P. aeruginosa (n=20) for ciprofloxacin, levofloxacin and garenoxacin. MPC results were 2-to-8 fold higher than MIC or MBC results. Ciprofloxacin MPC results for E.coli, C. freundii, E. cloacae, K. pneumoniae, and P. aeruginosa were 0.5, 2, 1, 1, and 4 μg/ml, respectively. Levofloxacin, MPC results were were 1, 2, 4, 1, and 16 μg/ml, respectively. Garenoxacin, MPC were 1, 8, >8, 4, and >32 μg/ml, respectively. Garenoxacin had the highest MIC and MPC results and was the least active compound tested against isolates of C. freundii, E. cloacae, and P. aeruginosa. These data support the rational use of quinolones in the treatments of urinary tract infections and suppression of resistance. Incorporation of the MPC measurement into dosing strategies may preserve the longevity of antimicrobial compounds for future infectious diseases. iv ACKNOWLEDGEMENTS As with any major undertaking there are many individuals and organizations that have contributed to my thesis, to my education, and to my life, and it is now my great pleasure to take this opportunity to thank them. To be given an opportunity to answer a question and then to be entrusted with the confidence and support to find the answer is truly all that can be asked for by a graduate student of a supervisor. I am at a loss to express my gratitude to Dr. Joe Blondeau for the support, kindness, and education that I received under your leadership and realize that this help came during a very busy time in your career. I feel fortunate to have had a supervisor with the ability, willingness, and insight to help me reach my goals. I have been presented with unique opportunities during my graduate carrer which I will always be indebted to you for, I (and Conrad Hilton) appreciate the faith you showed in me, thank you! Finally I am grateful to you for your understanding and support in allowing me to leave the University during the final stages of my program to purse a clinical post-doctoral fellowship opportunity. I’m confident that your kindness will not go unrewarded. I would like to thank Drs. Deneer, Potter, Sanche, and Ziola for their assistance and advice. Committee members have suffered along with me during the writing stage of my thesis and their help was gratefully appreciated, the text itself has been significantly improved by their reviews. There is little doubt that I have “leaned” hard on my supervisor and committee members during this process and I would like to thank v those members who demonstrated understanding and patience along the way, I could not have realized my own objectives without the assistance of this group. I wish to thank Dr. Harry Deneer, and Dr Steve Sanche who also served as referees for me. My appreciation is also extended to Karl Drlica, Xilin Zhao and members of PHRI. Conversations, time and friendship extended to me throughout my program including time spent in New York were extremely helpful to me and influenced my research experience. I am grateful to Bayer, Bristol-Myers Squibb, Glaxco-SmithKline, and the College of Medicine at the University of Saskatchewan for provided financial support for research and travel to international meetings. I am especially grateful to Glenn Tillotson, Allan Westwood and Kathlene Gravelle for their help and support. Thanks also to the many students I have seen excel through the ranks, especially Leslie and Landon, for their “scientific input”, comic relief, and fun times. Thanks to my lab mates Shantelle, Deb, Marnie, Peter, Kelli as well as Mary Woodsworth and Karen Mochoruk. A special thanks is extended to Brad Cookson, Feric Fang, and Ajit Limaye at the University of Washington for “putting up with me” and for their understanding during this time. Finally I wish to thank my family especially my parents, for their unconditional support and absolute confidence in me and to Bina who was a constant friend. Their support of me made it possible for me to achieve success and for that I will be forever grateful. vi TABLE OF CONTENTS Page ii Permission to Use iii Abstract v Acknowledgements vii Table of Contents xiii List of Tables xv List of Figures xviii Abbreviations Used 1 1.0 Introduction 1 1.1 Quinolone Antibiotics 2 1.2 History and Development of Quinolone Agents: Structure-Activity Relationships 11 1.3 Intracellular Quinolone Targets and Quinolone Action 13 1.4 Mechanisms of Quinolone Action 14 1.5 Mechanisms of Quinolone Resistance 17 1.6 Reduced Intracellular Concentration 18 1.7 Key Pharmacokinetic and Pharmacodynamic Factors for Fluorouinolone Antibioitcs 25 1.8 The Mutant-Prevention Concentraton (MPC): In vitro Measurement of the MPC and Experimental Determination of the Mutant-Selection Window 37 2.0 Materials and Methods vii 37 2.1 Standard Laboratory Methods 37 2.1.1 Isolate Collection and Identification 38 2.1.2 Storage of the Bacterial Isolates 39 2.2 Susceptibility Testing 39 2.2.1 Broth Microdilution 40 2.2.2 Broth Microdilution using CCCP 41 2.2.3 MBC Testing 41 2.2.4 E-Test 42 2.2.5 Vitek Results 43 2.2.6 Agar Dilution 43 2.3 Mutant-Prevention Concentration (MPC) 43 2.3.1 Inoculum Preparation and MPC Testing Procedure 47 2.3.2 Mutant Selection Curves 47 2.3.3 Viable Counts 48 2.4 Characterization of First-step Mutants 48 2.4.1 DNA Isolation, Amplification and Nucleotide Sequence Determination for S. pneumoniae 50 2.4.2 DNA Isolation, Amplification and Nucleotide Sequence Determination for Recovered Mutants of P. aeruginosa 51 2.4.3 Primer Preparation and Storage 51 2.4.4 Analysis of PCR Products 51 2.5 Pulsed-Field Gel Electrophoresis (PFGE) for Clinical Isolates of P. aeruginosa viii 51 2.5.1 DNA Extraction 51 2.5.2 Cell Disruption 52 2.5.3 Proteinase K Treatment 52 2.5.4 Inactivation of Proteinase K 52 2.5.5 Storage of Plugs 53 2.5.6 Restriction Endonuclease Digestion 53 2.5.7 Preparation of the Gels 53 2.5.8 Staining Procedure 54 2.6 Killing of S. pneumoniae by Fluoroquinolones Assessed with Conventional Kill Curves 55 2.7 Killing of P. aeruginosa by Ciprofloxacin and Levofloxacin Assessed with MPC-based Kill Curve Experiments 56 2.8 Ciprofloxacin and Levofloxacin Efficacy in a Rat Abscess Model of P.
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