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Aeromonas Salmonicida Epidemiologic Cutoff Values for Antimicrobial Agents Used in Aquaculture

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Aeromonas Salmonicida Epidemiologic Cutoff Values for Antimicrobial Agents Used in Aquaculture ABSTRACT Title of Document: DEVELOPMENT OF STANDARDIZED ANTIMICROBIAL SUSCEPTIBILITY TESTING METHODS AND AEROMONAS SALMONICIDA EPIDEMIOLOGIC CUTOFF VALUES FOR ANTIMICROBIAL AGENTS USED IN AQUACULTURE Ron A. Miller, Ph.D., 2007 Directed By: Adjunct Associate Professor Andrew S. Kane, College of Agriculture and Natural Resources- Department of Veterinary Medicine Pharmacokinetics describes the time course of drug absorption, distribution, metabolism and excretion. Pharmacodynamics is the relationship between unbound drug concentration over time and the resulting antimicrobial effect. Pharmacokinetic/ pharmacodynamic (PK/PD) indices quantify the relationship between pharmacokinetic parameters (i.e., area under the concentration-time curve, AUC) and microbiological parameters (i.e., minimal inhibitory concentrations, MICs), and are used to establish interpretive criteria or clinical breakpoints. The three primary PK/PD indices used are the AUC over 24 h at steady-state/MIC (AUCss/MIC), the peak concentration/MIC (Cmax/MIC), and the percentage of time over 24 hours that the drug concentration exceeds the MIC at steady-state pharmacokinetic conditions (T>MIC). These indices can be used to determine both appropriate dosage regimens and index magnitudes required for efficacy and reduced antimicrobial resistance emergence. The goal of this work was to determine the relevant PK/PD index target (AUCss/MIC) for oxytetracycline (OTC) against Aeromonas salmonicida, causative agent of furunculosis in salmonids. To achieve this goal we first established a standardized MIC testing method for aquatic bacterial pathogens, then used this method to determine the in vitro susceptibility cutoff concentration (epidemiologic cutoff value) for OTC (and three other antimicrobial agents) against 217 A. salmonicida isolates. We conducted additional in vivo studies using rainbow trout to monitor achievable serum OTC concentrations in both healthy and A. salmonicida-challenged fish. We confirmed OTC to be highly efficacious against a susceptible A. salmonicida strain in vivo, and through pharmacokinetics studies, calculated the OTC AUCss in healthy and challenged fish to be 27.2 and 20.1 μg·h/mL, respectively. The PK/PD index target reported in a neutropenic mouse model as the most applicable to the tetracyclines is an AUCss/MIC of ≥5. Either of the AUCss values divided by the current epidemiologic cutoff value for A. salmonicida isolates (1 μg/mL) yields a product greater than this AUCss/MIC target of ≥5. This work demonstrates PK/PD indices commonly used in studies in mammals to predict therapeutic efficacy can be applied in studies in fish. DEVELOPMENT OF STANDARDIZED ANTIMICROBIAL SUSCEPTIBILITY TESTING METHODS AND AEROMONAS SALMONICIDA EPIDEMIOLOGIC CUTOFF VALUES FOR ANTIMICROBIAL AGENTS USED IN AQUACULTURE By Ron A. Miller Dissertation submitted to the Faculty of the Graduate School of the University of Maryland, College Park, in partial fulfillment of the requirements for the degree of Doctor of Philosophy 2007 Advisory Committee: Adjunct Associate Professor Andrew S. Kane, Chair Adjunct Associate Professor Renate Reimschuessel Associate Professor Katherine S. Squibb Professor Jianghong Meng Extension Research Associate Ana M. Baya © Copyright by Ron A. Miller 2007 Dedication Erin, my sweet, thank you for your patience, encouragement, guidance, love and understanding. ii Acknowledgements I would first like to recognize Dr. Renate Reimschuessel for her incredible mentorship the past 6 years. You are an amazing teacher and advisor. Thank you for your exceptional guidance, honesty, and exceptional sense of humor. I also must thank Charles Gieseker and all the other scientists, managers, and staff in the FDA - Center for Veterinary Medicine’s Office of Research. Your generosity and willingness to always lend a helping hand has been very important to me, and for that I will always be grateful. I must recognize Dr. Andrew Kane for agreeing to serve as my major advisor and for your superb knack for troubleshooting and getting me and my project in the right direction. Lastly, I’d like to thank the other members of my graduate advisory committee, Drs. Ana Baya, Katherine Squibb and Jianghong Meng for their time, guidance, and for agreeing to serve on my committee. iii Table of Contents Dedication .......................................................................................................................... ii Acknowledgements ..........................................................................................................iii Table of Contents ............................................................................................................. iv List of Tables ................................................................................................................... vii List of Figures................................................................................................................... ix Chapter 1: Antimicrobial Agents Used in Aquaculture................................................ 1 Antimicrobial Agents Approved for Use in Aquaculture in the United States............... 1 Introduction................................................................................................................. 1 Oxytetracycline........................................................................................................... 3 Sulfadimethoxine-ormetoprim.................................................................................... 5 Florfenicol................................................................................................................... 6 Sulfamerazine ............................................................................................................. 7 Other Antimicrobial Agents Used in Aquaculture Worldwide....................................... 8 Quinolones .................................................................................................................. 8 Beta-lactams................................................................................................................ 9 Sulfonamides and Potentiated Sulfonamides............................................................ 10 Phenicols................................................................................................................... 11 Pharmacokinetics of Antimicrobial Agents Commonly Used in Aquaculture in the United States ................................................................................................................. 11 Pharmacokinetics ...................................................................................................... 11 Oxytetracycline......................................................................................................... 13 Sulfadimethoxine-ormetoprim.................................................................................. 16 Florfenicol................................................................................................................. 19 Antimicrobial Susceptibility Testing ............................................................................ 21 Current Status of Methods ........................................................................................ 21 Interpretive Criteria................................................................................................... 23 Chapter 2: Antimicrobial Resistance Mechanisms and Susceptibility Testing of Aquatic Isolates ............................................................................................................... 27 Introduction................................................................................................................... 27 Antimicrobial Resistance in the Aquatic Environment ................................................ 32 Why is there a need to monitor changes in resistance? ............................................ 32 Resistance Mechanisms and Associated Genes Identified in Aquatic Bacteria ....... 34 Antimicrobial Susceptibility Testing of Aquatic Bacteria............................................ 38 Introduction............................................................................................................... 38 Importance of Temperature for Susceptibility.......................................................... 38 Current Status of Disk Diffusion Methods ............................................................... 40 Current Status of Dilution Methods.......................................................................... 42 Future Needs and Challenges........................................................................................ 44 Interpretive Criteria................................................................................................... 44 Methods of AST for the Other Isolates..................................................................... 45 Acknowledgements....................................................................................................... 46 iv Chapter 3: Standardization of a broth microdilution susceptibility testing method to determine minimal inhibitory concentrations of aquatic bacteria............................. 47 Abstract......................................................................................................................... 47 Introduction................................................................................................................... 48 Materials and Methods.................................................................................................
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