Preface xv Acknowledgment xvii Editors xix Contributors xxi 1 Antibiotics: Groups and Properties 1 Philip Thomas Reeves 1.1 Introduction, 1 1.1.1 Identification, 1 1.1.2 Chemical Structure, 2 1.1.3 Molecular Formula, 2 1.

1.4 Composition of the Substance, 2 1.1.5 p K a, 2 1.1.6 UV Absorbance, 3 1.1.7 Solubility, 3 1.

1.8 Stability, 3 1.2 Antibiotic Groups and Properties, 3 1.2.1 Terminology, 3 1.2.2 Fundamental Concepts, 4 1.2.

3 Pharmacokinetics of Antimicrobial Drugs, 4 1.2.4 Pharmacodynamics of Antimicrobial Drugs, 5 1.2.4.1 Spectrum of Activity, 5 1.2.4.

2 Bactericidal and Bacteriostatic Activity, 6 1.2.4.3 Type of Killing Action, 6 1.2.4.4 Minimum Inhibitory Concentration and Minimum Bactericidal Concentration, 7 1.2.

4.5 Mechanisms of Action, 7 1.2.5 Antimicrobial Drug Combinations, 7 1.2.6 Clinical Toxicities, 7 1.2.7 Dosage Forms, 8 1.

2.8 Occupational Health and Safety Issues, 8 1.2.9 Environmental Issues, 8 1.3 Major Groups of Antibiotics, 8 1.3.1 Aminoglycosides, 8 1.3.

2 ß-Lactams, 10 1.3.3 Quinoxalines, 18 1.3.4 Lincosamides, 20 1.3.5 Macrolides and Pleuromutilins, 21 1.3.

6 Nitrofurans, 27 1.3.7 Nitroimidazoles, 28 1.3.8 Phenicols, 30 1.3.9 Polyether Antibiotics (Ionophores), 31 1.3.

10 Polypeptides, Glycopeptides, and Streptogramins, 35 1.3.11 Phosphoglycolipids, 36 1.3.12 Quinolones, 36 1.3.13 Sulfonamides, 44 1.3.

14 Tetracyclines, 45 1.4 Restricted and Prohibited Uses of Antimicrobial Agents in Food Animals, 52 1.5 Conclusions, 52 Acknowledgments, 53 References, 53 2 Pharmacokinetics, Distribution, Bioavailability, and Relationship to Antibiotic Residues 61 Peter Lees and Pierre-Louis Toutain 2.1 Introduction, 61 2.2 Principles of Pharmacokinetics, 61 2.2.1 Pharmacokinetic Parameters, 61 2.2.

2 Regulatory Guidelines on Dosage Selection for Efficacy, 64 2.2.3 Residue Concentrations in Relation to Administered Dose, 64 2.2.4 Dosage and Residue Concentrations in Relation to Target Clinical Populations, 66 2.2.5 Single-Animal versus Herd Treatment and Establishment of Withholding Time (WhT), 66 2.2.

6 Influence of Antimicrobial Drug (AMD) Physicochemical Properties on Residues and WhT, 67 2.3 Administration, Distribution, and Metabolism of Drug Classes, 67 2.3.1 Aminoglycosides and Aminocyclitols, 67 2.3.2 ß-Lactams: Penicillins and Cephalosporins, 69 2.3.3 Quinoxalines: Carbadox and Olaquindox, 71 2.

3.4 Lincosamides and Pleuromutilins, 71 2.3.5 Macrolides, Triamilides, and Azalides, 72 2.3.6 Nitrofurans, 73 2.3.7 Nitroimidazoles, 73 2.

3.8 Phenicols, 73 2.3.9 Polyether Antibiotic Ionophores, 74 2.3.10 Polypeptides, 75 2.3.11 Quinolones, 75 2.

3.12 Sulfonamides and Diaminopyrimidines, 77 2.3.13 Polymyxins, 79 2.3.14 Tetracyclines, 79 2.4 Setting Guidelines for Residues by Regulatory Authorities, 81 2.5 Definition, Assessment, Characterization, Management, and Communication of Risk, 82 2.

5.1 Introduction and Summary of Regulatory Requirements, 82 2.5.2 Risk Assessment, 84 2.5.2.1 Hazard Assessment, 88 2.5.

2.2 Exposure Assessment, 89 2.5.3 Risk Characterization, 90 2.5.4 Risk Management, 91 2.5.4.

1 Withholding Times, 91 2.5.4.2 Prediction of Withdholding Times from Plasma Pharmacokinetic Data, 93 2.5.4.3 International Trade, 93 2.5.

5 Risk Communication, 94 2.6 Residue Violations: Their Significance and Prevention, 94 2.6.1 Roles of Regulatory and Non-regulatory Bodies, 94 2.6.2 Residue Detection Programs, 95 2.6.2.

1 Monitoring Program, 96 2.6.2.2 Enforcement Programs, 96 2.6.2.3 Surveillance Programs, 97 2.6.

2.4 Exploratory Programs, 97 2.6.2.5 Imported Food Animal Products, 97 2.6.2.6 Residue Testing in Milk, 97 2.

7 Further Considerations, 98 2.7.1 Injection Site Residues and Flip-Flop Pharmacokinetics, 98 2.7.2 Bioequivalence and Residue Depletion Profiles, 100 2.7.3 Sales and Usage Data, 101 2.7.

3.1 Sales of AMDs in the United Kingdom, 2003?2008, 101 2.7.3.2 Comparison of AMD Usage in Human and Veterinary Medicine in France, 1999?2005, 102 2.7.3.3 Global Animal Health Sales and Sales of AMDs for Bovine Respiratory Disease, 103 References, 104 3 Antibiotic Residues in Food and Drinking Water, and Food Safety Regulations 111 Kevin J.

Greenlees, Lynn G. Friedlander, and Alistair Boxall 3.1 Introduction, 111 3.2 Residues in Food?Where is the Smoking Gun?, 111 3.3 How Allowable Residue Concentrations Are Determined, 113 3.3.1 Toxicology?Setting Concentrations Allowed in the Human Diet, 113 3.3.

2 Setting Residue Concentrations for Substances Not Allowed in Food, 114 3.3.3 Setting Residue Concentrations Allowed in Food, 114 3.3.3.1 Tolerances, 115 3.3.3.

2 Maximum Residue Limits, 116 3.3.4 International Harmonization, 117 3.4 Indirect Consumer Exposure to Antibiotics in the Natural Environment, 117 3.4.1 Transport to and Occurrence in Surface Waters and Groundwaters, 119 3.4.2 Uptake of Antibiotics into Crops, 119 3.

4.3 Risks of Antibiotics in the Environment to Human Health, 120 3.5 Summary, 120 References, 121 4 Sample Preparation: Extraction and Clean-up 125 Alida A. M. (Linda) Stolker and Martin Danaher 4.1 Introduction, 125 4.2 Sample Selection and Pre-treatment, 126 4.3 Sample Extraction, 127 4.

3.1 Target Marker Residue, 127 4.3.2 Stability of Biological Samples, 127 4.4 Extraction Techniques, 128 4.4.1 Liquid?Liquid Extraction, 128 4.4.

2 Dilute and Shoot, 128 4.4.3 Liquid?Liquid Based Extraction Procedures, 129 4.4.3.1 QuEChERS, 129 4.4.3.

2 Bipolarity Extraction, 129 4.4.4 Pressurized Liquid Extraction (Including Supercritical Fluid Extraction), 130 4.4.5 Solid Phase Extraction (SPE), 131 4.4.5.1 Conventional SPE, 131 4.

4.5.2 Automated SPE, 132 4.4.6 Solid Phase Extraction-Based Techniques, 133 4.4.6.1 Dispersive SPE, 133 4.

4.6.2 Matrix Solid Phase Dispersion, 134 4.4.6.3 Solid Phase Micro-extraction, 135 4.4.6.

4 Micro-extraction by Packed Sorbent, 137 4.4.6.5 Stir-bar Sorptive Extraction, 137 4.4.6.6 Restricted-Access Materials, 138 4.4.

7 Solid Phase Extraction-Based Selective Approaches, 138 4.4.7.1 Immunoaffinity Chromatography, 138 4.4.7.2 Molecularly Imprinted Polymers, 139 4.4.

7.3 Aptamers, 140 4.4.8 Turbulent-Flow Chromatography, 140 4.4.9 Miscellaneous, 142 4.4.9.

1 Ultrafiltration, 142 4.4.9.2 Microwave-Assisted Extraction, 142 4.4.9.3 Ultrasound-Assisted Extraction, 144 4.5 Final Remarks and Conclusions, 144 References, 146 5 Bioanalytical Screening Methods 153 Sara Stead and Jacques Stark 5.

1 Introduction, 153 5.2 Microbial Inhibition Assays, 154 5.2.1 The History and Basic Principles of Microbial Inhibition Assays, 154 5.2.2 The Four-Plate Test and the New Dutch Kidney Test, 156 5.2.3 Commercial Microbial Inhibition Assays for Milk, 156 5.

2.4 Commercial Microbial Inhibition Assays for Meat-, Egg-, and Honey-Based Foods, 159 5.2.5 Further Developments of Microbial Inhibition Assays and Future Prospects, 160 5.2.5.1 Sensitivity, 160 5.2.

5.2 Test Duration, 161 5.2.5.3 Ease of Use, 161 5.2.5.4 Automation, 161 5.

2.5.5 Pre-treatment of Samples, 162 5.2.5.6 Confirmation/Class-Specific Identification, 163 5.2.6 Conclusions Regarding Microbial Inhibition Assays, 164 5.

3 Rapid Test Kits, 164 5.3.1 Basic Principles of Immunoassay Format Rapid Tests, 164 5.3.2 Lateral-Flow Immunoassays, 165 5.3.2.1 Sandwich Format, 166 5.

3.2.2 Competitive Format, 166 5.3.3 Commercial Lateral-Flow Immunoassays for Milk, Animal Tissues, and Honey, 168 5.3.4 Receptor-Based Radioimmunoassay: Charm II System, 170 5.3.

5 Basic Principles of Enzymatic Tests, 171 5.3.5.1 The Penzyme Milk Test, 171 5.3.5.2 The Delvo-X-PRESS, 172 5.3.

6 Conclusions Regarding Rapid Test Kits, 174 5.4 Surface Plasmon Resonance (SPR) Biosensor Technology, 174 5.4.1 Basic Principles of SPR Biosensor, 174 5.4.2 Commercially Available SPR Biosensor Applications for Milk, Animal Tissues, Feed, and Honey, 175 5.4.3 Conclusions Regarding Surface Plasmon Resonance (SPR) Technology, 176 5.

5 Enzyme-Linked Immunosorbent Assay (ELISA), 178 5.5.1 Basic Principles of ELISA, 178 5.5.2 Automated ELISA Systems, 178 5.5.3 Alternative Immunoassay Formats, 179 5.5.

4 Commercially Available ELISA Kits for Antibiotic Residues, 179 5.5.5 Conclusions Regarding ELISA, 180 5.6 General Considerations Concerning the Performance Criteria for Screening Assays, 181 5.7 Overall Conclusions on Bioanalytical Screening Assays, 181 Abbreviations, 182 References, 182 6 Chemical Analysis: Quantitative and Confirmatory Methods 187 Jian Wang and Sherri B. Turnipseed 6.1 Introduction, 187 6.2 Single-Class and Multi-class Methods, 187 6.

3 Chromatographic Separation, 195 6.3.1 Chromatographic Parameters, 195