Mayers Antimicrobial Drug Resistance

Mechanisms of Drug Resistance, Volume 1
1. Auflage 2009
ISBN: 978-1-59745-180-2
Verlag: Humana Press
Format: PDF
Kopierschutz: Adobe DRM (»Systemvoraussetzungen)

E-Book, Englisch, 678 Seiten

This ? rst edition of Antimicrobial Drug Resistance grew out of a desire by the editors and authors to have a comprehensive resource of information on antimicrobial drug resistance that encompassed the current information available for bacteria, fungi, protozoa and viruses. We believe that this information will be of value to clinicians, epidemiologists, microbiologists, virologists, parasitologists, public health authorities, medical students and fellows in training. We have endeavored to provide this information in a style which would be accessible to the broad community of persons who are concerned with the impact of drug resistance in our cl- ics and across the broader global communities. Antimicrobial Drug Resistance is divided into Volume 1 which has sections covering a general overview of drug resistance and mechanisms of drug resistance ? rst for classes of drugs and then by individual microbial agents including bacteria, fungi, protozoa and viruses. Volume 2 addresses clinical, epidemiologic and public health aspects of drug resistance along with an overview of the conduct and interpretation of speci? c drug resistance assays. Together, these two volumes offer a comprehensive source of information on drug resistance issues by the experts in each topic.

Autoren/Hrsg.

Mayers, Douglas

Inhaltsverzeichnis

1;Preface;5
2;Table of Contents Antimicrobial Drug Resistance Volume 1;6
3;Contributors;13
4;Part I: General Overview;25
4.1;Chapter 1 History of Drug-Resistant Microbes;26
4.2;Chapter 2 Evolutionary Biology of Drug Resistance;31
4.2.1;1 Introduction;31
4.2.2;2 Variability: The Substrate of Evolution of Drug Resistance;31
4.2.2.1;2.1 The Complexity of Antibiotic Action and the Variety of Resistance Phenotypes;31
4.2.2.1.1;2.1.1 Adaptation without Change: Redundancy and Degeneracy of Bacterial Systems;32
4.2.2.1.2;2.1.2 Phenotypic Tolerance;32
4.2.2.2;2.2 The Source of Antibiotic-Resistance Genes;33
4.2.2.2.1;2.2.1 Origin of Drug Resistance: The Case of Beta-Lactamases;34
4.2.2.3;2.3 Global Stress Regulation and Antibiotic Resistance;35
4.2.2.4;2.4 Genetic Variation: Mutation;36
4.2.2.4.1;2.4.1 Mutation Frequency and Mutation Rate;36
4.2.2.4.2;2.4.2 Hyper-Mutation;36
4.2.2.4.3;2.4.3 Antibiotics Inducing Mutations;37
4.2.2.5;2.5 Genetic Variation: Gene Recombination;37
4.2.2.6;2.6 Genetic Variation: Modularization;38
4.2.2.7;2.7 Horizontal Genetic Transfer and Bacterial Variation;39
4.2.2.7.1;2.7.1 Plasmids and Drug Resistance Evolution;39
4.2.2.7.2;2.7.2 Transposable Elements;40
4.2.2.7.3;2.7.3 Phages;40
4.2.2.8;2.8 Genetic Variation: Clonalization;41
4.2.2.9;2.9 Generation of Variation in Response to Antibiotic Stress;41
4.2.2.10;2.10 Phenotypic Variation and Genetic Variation: the Baldwin Effect;42
4.2.3;3 Selection: The Mechanism of Evolution of Drug Resistance;42
4.2.3.1;3.1 Selection by Low Antibiotic Concentrations;42
4.2.3.2;3.2 Concentration-Specifi c Selection: the Selective Window;43
4.2.3.3;3.3 Antibiotic Gradients in Antibiotic Selection;43
4.2.3.4;3.4 Fluctuating Antibiotic Environments;44
4.2.3.5;3.5 Selection Towards Multi-Resistance: Genetic Capitalism;44
4.2.4;4 Evolution of Drug Resistance: Future Prospects;45
4.2.4.1;4.1 Units of Variation and Units of Selection;45
4.2.4.2;4.2 The Limits of Drug-Resistance Evolution;46
4.2.4.2.1;4.2.1 Saturation Constraints, Short-Sighted Evolution;46
4.2.4.2.2;4.2.2 Minimizing the Costs of Evolvability;46
4.2.4.2.3;4.2.3 Cost of Antibiotic Resistance;46
4.2.4.3;4.3 Epidemiology and Evolution of Antibiotic Resistance;47
4.2.4.3.1;4.3.1 Resistance, Epidemics, Endemics, and Allodemics;47
4.2.4.3.2;4.3.2 Resistance as a Colonization Factor;48
4.2.4.3.3;4.3.3 Biogeography and Local Biology of Antibiotic Resistance;49
4.2.4.3.4;4.3.4 Antibiotics as Ecosystem-Damaging Agents: the Role of Resistance;49
4.2.4.3.5;4.3.5 Might Evolution of Antibiotic Resistance Be Predicted?;49
4.2.5;References;51
4.3;Chapter 3 Pharmacology of Drug Resistance;55
4.3.1;1 Introduction;55
4.3.2;2 Resistance Defi ned by Breakpoint: Good Clinical Response for “Sensitive”;55
4.3.2.1;2.1 Goal of Therapy;55
4.3.2.2;2.2 Protein Binding;56
4.3.2.3;2.3 Distribution of Drug Exposure;57
4.3.2.4;2.4 Distribution of MIC Values;57
4.3.2.5;2.5 Integration of Factors for Dose Choice and Sensitivity Breakpoint;58
4.3.3;3 Resistance Defi ned by Mechanism;59
4.3.4;4 Suppression of Resistance by Dosing;60
4.3.5;5 Choosing a Dose for Suppression of Resistant Subpopulation Amplifi cation;62
4.3.6;6 Summary;63
4.3.7;References;63
4.4;Chapter 4 Antimicrobial Resistance Versus the Discovery and Development of New Antimicrobials;65
4.4.1;1 Introduction;65
4.4.2;2 Antibiotics and the Pharmaceutical Industry;65
4.4.3;3 The Rise in Resistance to Penicillin;65
4.4.3.1;3.1 The Golden Era;66
4.4.4;4 Microbial Genomics: The Failure to Deliver and the Hope for the Future;66
4.4.5;5 Medical Need, Antimicrobial Resistance, and the Anti-Infective Marketplace;67
4.4.6;6 The Regulatory Environment for Antibacterials;68
4.4.7;7 Large Pharmaceutical Companies Consolidate and Abandon Antibacterial Discovery while Biotechnology Enters the Field;69
4.4.8;8 The Future of Antibacterial Research;70
4.4.9;9 Conclusions;70
4.4.10;References;71
5;Part II: General Mechanisms of Drug Resistance;73
5.1;Chapter 5 Genetic Mechanisms of Transfer of Drug Resistance;74
5.1.1;1 Introduction;83
5.1.2;2 Conjugative Plasmids;74
5.1.2.1;2.1 DNA Replication;74
5.1.2.2;2.2 Partition and Control of Copy Number;75
5.1.2.3;2.3 Conjugative Transfer;75
5.1.2.4;2.4 Antibiotic Resistance and Other Auxiliary Genes;75
5.1.3;3 Composite Transposons;75
5.1.3.1;3.1 Structure and Mechanism;75
5.1.3.2;3.2 Newer Elements and Their Antibiotic Resistance Genes;77
5.1.4;4 Simple Transposons;77
5.1.4.1;4.1 Tn3 and TEM Beta-Lactamase Genes;77
5.1.4.2;4.2 Tn1546 and Vancomycin Resistance;78
5.1.4.3;4.3 Site-Specifi c Transposons: Tn7 and the Tn5053 Family;78
5.1.5;5 Conjugative Transposons;78
5.1.5.1;5.1 Tn916-Like Elements and Their Antibiotic Resistance Genes;78
5.1.5.2;5.2 Mechanism of Transfer;78
5.1.5.3;5.3 Related Elements;79
5.1.6;6 Integrons and ISCR Elements;79
5.1.6.1;6.1 Class 1 Integrons;79
5.1.6.2;6.2 Recent Evolution of Class 1 Integrons;80
5.1.6.3;6.3 Antibiotic Resistance Genes Carried by Integrons;81
5.1.6.4;6.4 Gene Expression in Class 1 Integrons;81
5.1.6.5;6.5 Chromosomal Integrons;81
5.1.6.6;6.6 Origin of Integron Cassettes;82
5.1.6.7;6.7 CR Elements;82
5.1.6.8;6.8 Antibiotic Resistance Genes Carried by CR Elements;82
5.1.7;7 Outlook;82
5.1.8;References;83
5.2;Chapter 6 Mutations as a Basis of Antimicrobial Resistance;86
5.2.1;1 Prefatory Remarks;86
5.2.2;2 Genetic Diversity and Mutator Strains;86
5.2.3;3 Mismatch Repair-Defi cient Permanent Hypermutators;87
5.2.4;4 Transient Hypermutators and the SOS System;87
5.2.5;5 Antimicrobial Resistance Determinants;88
5.2.6;6 Beta-Lactam Resistance Mediated by Low-Affi nity Penicillin Binding Proteins;88
5.2.7;7 Quinolone-Resistance Determining Region in Fluoroquinolone-Resistant Bacteria;89
5.2.8;8 Streptomycin Resistance and Mycobacteria;89
5.2.9;9 Rifampin Resistance;89
5.2.10;10 Fluoroquinolone Resistance Caused by Overexpression of Active Effl ux Pumps;90
5.2.11;11 Constitutive Tetracycline Resistance due to a Mutated Repressor Gene;90
5.2.12;12 Constitutive and Inducible Glycopeptide Resistance Caused by Point Mutations in the Regulatory System;90
5.2.13;13 Unique Regulation of Inducible Macrolide Resistance by Translational Attenuation;91
5.2.14;14 b -Lactam Resistance Caused by AmpC Beta -Lactamase Hyperproduction;91
5.2.15;15 Point Mutations in Acquired Resistance Genes: The New-Generation Beta -Lactamases;91
5.2.16;16 The G238S ESBL Mutation;92
5.2.17;17 Inhibitor-Resistant TEMs;92
5.2.18;18 Complex Mutants of TEM;93
5.2.19;19 CTX-M;93
5.2.20;20 Global Suppressors;93
5.2.21;21 OXA;94
5.2.22;22 Concluding Remarks;94
5.2.23;References;94
5.3;Chapter 7 Target-Mediated Antibacterial Resistance;96
5.3.1;1 Introduction;96
5.3.2;2 Point Mutations that Create Resistance;96
5.3.3;3 Mosaic Genes;98
5.3.4;4 Target Overproduction;98
5.3.5;5 Target Substitution;98
5.3.6;6 Target Modifification or Protection;99
5.3.7;7 Conclusion;100
5.3.8;References;100
5.4;Chapter 8 Biochemical Logic of Antibiotic Inactivation and Modification;102
5.4.1;1 Introduction;102
5.4.2;2 Destruction of Antibiotics;102
5.4.2.1;2.1 Beta-Lactam Antibiotics;103
5.4.2.2;2.2 Fosfomycin;104
5.4.2.3;2.3 Macrolide Antibiotics;105
5.4.2.4;2.4 Type B Streptogramins;106
5.4.2.5;2.5 Tetracycline;107
5.4.3;3 Antibiotic Modification;107
5.4.3.1;3.1 Aminoglycosides;108
5.4.3.1.1;3.1.1 Aminoglycoside Acetyltransferases (AAC Family);109
5.4.3.1.2;3.1.2 Aminoglycoside Phosphotransferases (APH Family);110
5.4.3.1.3;3.1.3 Aminoglycoside Nucleotidyltransferases (ANT Family);110
5.4.3.2;3.2 Macrolides;110
5.4.3.2.1;3.2.1 Macrolide Kinases (Mph Family);111
5.4.3.2.2;3.2.2 Macrolide Glycosyltransferases (Mgt Family);112
5.4.3.3;3.3 Rifamycins;112
5.4.3.3.1;3.3.1 ADP-Ribosyltransferases (ARR Family);112
5.4.3.3.2;3.3.2 Rifampicin Kinases;113
5.4.3.3.3;3.3.3 Rifampicin Glycosyltransferases;113
5.4.4;4 Summary and Conclusions;113
5.4.5;References;114
5.5;Chapter 9 Antibiotic Resistance Due to Reduced Uptake;117
5.5.1;1 Introduction;117
5.5.2;2 Envelope Structure;117
5.5.2.1;2.1 Cytoplasmic Membrane;117
5.5.2.2;2.2 Periplasm/Peptidoglycan;118
5.5.2.3;2.3 Outer Membrane;119
5.5.2.4;2.4 Mycobacterial Cell Envelope;120
5.5.2.5;2.5 Capsule;121
5.5.3;3 Intrinsic Resistance;121
5.5.3.1;3.1 Restricted Permeability;121
5.5.3.1.1;3.1.1 Gram-Negative Bacteria;121
5.5.3.2;3.2 Mycobacteria;122
5.5.3.3;3.3 Effl ux;122
5.5.4;4 Antibiotic Penetration and Resistance Mechanisms;123
5.5.4.1;4.1 Porin Pathway;123
5.5.4.2;4.2 Self-Promoted Uptake and Regulatory Mutants;124
5.5.4.3;4.3 Hydrophobic Pathway;126
5.5.4.4;4.4 Inner Membrane Transporters;126
5.5.5;5 Synergy;127
5.5.6;6 Conclusions;127
5.5.7;References;127
5.6;Chapter 10 Transport Mechanisms of Resistance to Drugs and Toxic Metals;131
5.6.1;1 Introduction;131
5.6.2;2 H+/Na+-Driven Antiporters;131
5.6.3;3 Structural Analysis of Antiporters;132
5.6.4;4 Tripartite Pumps;133
5.6.5;5 ABC Transporters;133
5.6.6;6 Structural Analysis of ABC ATPases;134
5.6.7;7 Metal Efflux Systems: P-Type ATPases, RND Transporters and the Arsab Pump;135
5.6.8;8 Drug Resistance Can Result from Decreased Uptake;136
5.6.9;9 Circumventing Drug Effl ux;137
5.6.10;10 Reversing P-Glycoprotein-Mediated Multidrug Resistance;137
5.6.11;11 Reversal of Bacterial Multidrug Resistance;137
5.6.12;12 The Future of Multidrug Resistance Inhibition;137
5.6.13;References;138
5.7;Chapter 11 The Functional Resistance of Bacterial Biofi lms;141
5.7.1;1 Pathogenic Bacterial Communities;141
5.7.2;2 Stealthy Infections: Flying Below Our Radar;141
5.7.3;3 Biofi lm Structure and Physiology;143
5.7.4;4 Resisting Host Defense;143
5.7.5;5 Why Antimicrobials Fail: Learning from Planktonic Cultures;143
5.7.6;6 Biofi lm-Specifi c Resistance;145
5.7.7;7 Trading Posts for Resistance Genes;147
5.7.8;8 Treating Biofilm Infections;147
5.7.9;9 Conclusion;148
5.7.10;References;148
6;Part III: Bacterial Drug Resistance - Mechanisms;152
6.1;Chapter 12 The Importance of Beta-Lactamases to the Development of New Beta-Lactams;153
6.1.1;1 Introduction;153
6.1.2;2 Hydrolytic Activity;153
6.1.3;3 Beta-lactamase Origins;154
6.1.4;4 Classification Schemes;154
6.1.5;5 Historical Development of Beta-Lactam Antibiotics;156
6.1.6;6 Emergence of Beta-Lactamase Families;158
6.1.6.1;6.1 Gram-Positive Bacteria;158
6.1.6.2;6.2 Gram-Negative Bacteria;158
6.1.7;7 Future Directions;159
6.1.8;References;159
6.2;Chapter 13 Penicillin-Binding Proteins and Beta-Lactam Resistance;163
6.2.1;1 What Are PBPs?;163
6.2.2;2 Classification of PBPs;164
6.2.3;3 Physiological Function of PBPs;165
6.2.4;4 PBP-Based Beta-Lactam Resistance;166
6.2.4.1;4.1 Staphylococcus aureus;166
6.2.4.2;4.2 Enterococci;169
6.2.4.3;4.3 Streptococcus pneumoniae;172
6.2.4.4;4.4 Neisseria;179
6.2.4.5;4.5 Other Pathogens;179
6.2.5;5 Are the PBPs Sustainable Targets?;181
6.2.6;References;182
6.3;Chapter 14 Aminoglycosides: Mechanisms of Action and Resistance;189
6.3.1;1 Antimicrobial Mechanism of Action;189
6.3.2;2 Mechanism of Drug Resistance;191
6.3.2.1;2.1 Ribosomal Mutations;191
6.3.2.2;2.2 16s rRNA Methylation;191
6.3.2.3;2.3 Effl ux-Mediated Resistance;192
6.3.2.4;2.4 Enzymatic Drug Modifi cation;192
6.3.2.4.1;2.4.1 Aminoglycoside Adenylyltransferases;193
6.3.2.4.2;2.4.2 Aminoglycoside Phosphotransferases;194
6.3.2.4.3;2.4.3 Aminoglycoside Acetyltransferases;194
6.3.3;3 Mechanism of the Spread of Resistance;196
6.3.4;4 Cross-Resistance;197
6.3.5;5 Alternative Agents;197
6.3.6;References;197
6.4;Chapter 15 Tetracycline and Chloramphenicol Resistance Mechanisms;200
6.4.1;1 Introduction;208
6.4.1.1;1.1 Tetracycline Resistance;200
6.4.1.2;1.2 Chloramphenicol Resistance;200
6.4.2;2 Mechanisms of Tetracycline Resistance;201
6.4.2.1;2.1 Tetracycline Resistance Due to Efflux Proteins;201
6.4.2.2;2.2 Tetracycline Resistance due to Ribosomal Protection Proteins;204
6.4.2.3;2.3 Tetracycline Resistance due to Enzymatic Inactivation;204
6.4.2.4;2.4 Other/Unknown Mechanisms of Resistance;204
6.4.2.5;2.5 Tetracycline Resistance due to Mutations;205
6.4.3;3 Mechanisms of Chloramphenicol Resistance;205
6.4.3.1;3.1 Chloramphenicol Resistance due to Chloramphenicol O-Acetyltransferases;205
6.4.3.2;3.2 Chloramphenicol Resistance due to Specific Exporters;205
6.4.3.3;3.3 Chloramphenicol Resistance due to Multidrug Transporters, Permeability Barriers, Mutations, Phosphorylation, or Target Site Methylation;206
6.4.4;4 Distribution of Resistance Genes;206
6.4.4.1;4.1 Distribution of Tetracycline Genes;206
6.4.4.2;4.2 Distribution of Chloramphenicol Resistance Genes;207
6.4.5;5 Conclusion;208
6.4.6;References;208
6.5;Chapter 16 Fluoroquinolone Resistance in Bacteria;211
6.5.1;1 Introduction;211
6.5.2;2 Gram-Negative Bacteria;212
6.5.2.1;2.1 Target-Mediated Resistance;213
6.5.2.2;2.2 Decreased Outer Membrane Permeability;214
6.5.2.3;2.3 Effl ux-Related Resistance;214
6.5.2.4;2.4 Plasmid-Mediated Quinolone Resistance;216
6.5.2.5;2.5 Enzymatic Modifi cation of Quinolones;216
6.5.3;3 Gram-Positive Bacteria;216
6.5.3.1;3.1 Target-Mediated Resistance;217
6.5.3.2;3.2 Effl ux-Related Resistance;217
6.5.4;4 Means to Limit or Overcome Quinolone Resistance;218
6.5.5;References;219
6.6;Chapter 17 Plasmid-Mediated Quinolone Resistance;222
6.6.1;References;224
6.7;Chapter 18 Macrolides and Lincosamides;226
6.7.1;1 Introduction;226
6.7.2;2 Mode of Action of Macrolides and Lincosamides;226
6.7.3;3 Spectrum of Activity;227
6.7.4;4 Mechanisms of Resistance to Lincosamides and Clinical Implications;228
6.7.4.1;4.1 Ribosomal Methylation;228
6.7.4.1.1;4.1.1 erm Genes;228
6.7.4.1.2;4.1.2 Regulation of Erm Genes Expression;229
6.7.4.1.2.1;Inducible Resistance;229
6.7.4.1.2.2;Constitutive Resistance;230
6.7.4.1.3;4.1.3 Clindamycin for Infections Due to S. aureus with the MLSB Inducible Phenotype?;230
6.7.4.2;4.2 Ribosomal Mutations;231
6.7.4.3;4.3 Enzymatic Modifi cation of Macrolides;231
6.7.4.4;4.4 Enzymatic Modifi cation of Lincosamides;231
6.7.4.4.1;4.4.1 Expression of the lnu Genes;232
6.7.4.5;4.5 Effl ux;232
6.7.5;5 Report of Susceptibility Tests by the Laboratory;233
6.7.5.1;5.1 Staphylococci;233
6.7.5.1.1;5.1.1 Strains Resistant to Erythromycin but Susceptible to Clindamycin;233
6.7.5.1.2;5.1.2 Strains Susceptible to Erythromycin but Resistant to Lincosamides;233
6.7.5.2;5.2 Other Organisms;234
6.7.6;6 Conclusion;234
6.7.7;References;234
6.8;Chapter 19 Mechanism of Resistance in Metronidazole;237
6.8.1;Mechanism of Resistance in Metronidazole;237
6.8.1.1;1 Antimicrobial Mechanism of Action;237
6.8.1.2;2 Mechanism of Resistance;237
6.8.1.2.1;2.1 Bacteroides;237
6.8.1.2.2;2.2 Helicobacter pylori;238
6.8.1.2.3;2.3 Trichomonas;238
6.8.1.2.4;2.4 Clostridium spp.;239
6.8.1.2.5;2.5 Entamoeba and Giardia;239
6.8.1.3;3 Cross-Resistance;239
6.8.1.4;4 Mechanism of Spread of Resistance;239
6.8.1.5;5 Alternative Agents;239
6.8.1.5.1;5.1 Helicobacter Pylori;239
6.8.1.5.2;5.2 Trichomonas Vaginalis;239
6.8.1.5.3;5.3 Giardia;240
6.8.1.6;References;240
6.9;Chapter 20 Glycopeptide Resistance in Enterococci;242
6.9.1;1 Enterococci;242
6.9.2;2 Glycopeptides;242
6.9.3;3 Glycopeptide Resistance in Enterococci;242
6.9.4;4 The van Alphabet;243
6.9.4.1;4.1 Glycopeptide Resistance Due to Synthesis of Modified Peptidoglycan Precursors Ending in D-Ala-D-Lac;243
6.9.4.1.1;4.1.1 VanA;243
6.9.4.1.2;4.1.2 VanB;244
6.9.4.1.3;4.1.3 VanD;245
6.9.4.2;4.2 Glycopeptide Resistance Due to Synthesis of Modified Peptidoglycan Precursors Ending in D-Ala-D-Ser;246
6.9.4.2.1;4.2.1 VanC;246
6.9.4.2.2;4.2.2 VanE;247
6.9.4.2.3;4.2.3 VanG;248
6.9.5;5 Vancomycin-dependent Enterococci;248
6.9.6;6 Origin of the Vancomycin Resistance Genes;248
6.9.6.1;6.1 Acquired D-Ala:D-Lac Ligases;248
6.9.6.2;6.2 Acquired D-Ala:D-Ser Ligases;249
6.9.7;7 Transfer of VanA-Type Resistance to S. aureus;250
6.9.8;References;250
6.10;Chapter 21 Streptogramin;254
6.10.1;1 Class;254
6.10.2;2 Mechanism of Action;254
6.10.3;3 Mechanisms of Streptogramin Resistance;254
6.10.4;4 Streptogramin Resistance and the Epidemiology of MLSB;256
6.10.5;References;256
6.11;Chapter 22 Resistance to Linezolid;259
6.11.1;1 Oxazolidinones: A Brief Description of Chemistry;267
6.11.2;2 Mechanism of Action;259
6.11.3;3 Mechanisms of Resistance;261
6.11.3.1;3.1 Mutations Affecting 23S rRNA;261
6.11.3.2;3.2 Other Mechanisms;262
6.11.4;4 Activity of Linezolid Against Clinical Bacterial Isolates;262
6.11.5;5 Linezolid Resistance Among Clinical Isolates;264
6.11.5.1;5.1 Comparative Clinical Studies;264
6.11.5.2;5.2 Compassionate Use Program;265
6.11.5.3;5.3 Independent Observations of Resistance to Linezolid;265
6.11.5.3.1;5.3.1 Enterococci;265
6.11.5.3.2;5.3.2 Staphylococci;265
6.11.5.3.3;5.3.3 Other Organisms;266
6.11.6;6 Clinical Signifi cance of Linezolid Resistance;266
6.11.6.1;6.1 Enterococci;266
6.11.6.2;6.2 Staphylococci;266
6.11.7;7 Conclusions;267
6.11.8;References;267
6.12;Chapter 23 Sulfonamides and Trimethoprim;270
6.12.1;1 Introduction;270
6.12.2;2 Chromosomal Resistance to Sulfonamides;271
6.12.3;3 Plasmid-Borne Resistance to Sulfonamides;274
6.12.4;4 Chromosomal Resistance to Trimethoprim;275
6.12.5;5 Plasmid-Borne Resistance to Trimethoprim;276
6.12.6;6 Conclusions;277
6.12.7;References;278
6.13;Chapter 24 Mechanisms of Action and Resistance of Antimycobacterial Agents;282
6.13.1;1 Introduction;282
6.13.2;2 Isoniazid;282
6.13.2.1;2.1 Mechanism of Action;283
6.13.2.2;2.2 Mechanisms of Drug Resistance;285
6.13.2.3;2.3 katG;285
6.13.2.4;2.4 inhA;285
6.13.2.5;2.5 Other Genes;285
6.13.3;3 Rifampin and Other Rifamycins;286
6.13.3.1;3.1 Mechanism of Action;286
6.13.3.2;3.2 Mechanism of Resistance;286
6.13.4;4 Pyrazinamide;287
6.13.4.1;4.1 Mechanism of Action;287
6.13.4.2;4.2 Mechanisms of Resistance;288
6.13.5;5 Ethambutol;288
6.13.5.1;5.1 Mechanism of Action;288
6.13.5.2;5.2 Mechanisms of Resistance;289
6.13.6;6 Aminoglycosides;289
6.13.7;7 Fluoroquinolones;290
6.13.8;8 Macrolides;291
6.13.8.1;8.1 Cross-Resistance of Antimycobacterial Agents;292
6.13.8.2;8.2 Mechanism of Spread of Resistance;292
6.13.8.3;8.3 Alternative Agents;293
6.13.9;References;294
7;Part IV: Fungal Drug Resisrance - Mechanisms;281
7.1;Chapter 25 Amphotericin B: Polyene Resistance Mechanisms;303
7.1.1;1 Introduction;311
7.1.1.1;1.1 Epidemiology of Polyene Resistance;304
7.1.1.2;1.2 Emergence of Polyene Resistance;305
7.1.2;2 Mechanism of Action of Amphotericin B;305
7.1.2.1;2.1 Interaction with Sterols in the Fungal Cell Membrane;306
7.1.2.2;2.2 Oxidative Damage to the Fungal Cell Membrane;307
7.1.3;3 Mechanisms of Resistance;307
7.1.3.1;3.1 Polyene Resistance in Experimentally Induced Mutants and Clinical Isolates;307
7.1.3.2;3.2 Resistance to Oxidation;308
7.1.3.3;3.3 Biofi lm Formation;310
7.1.3.4;3.4 Fatty Acid Composition;310
7.1.3.5;3.5 Cell Wall Alterations;310
7.1.3.6;3.6 Yeast Cell Cycle;310
7.1.4;4 Conclusions;310
7.1.5;References;311
7.2;Chapter 26 Fungal Drug Resistance: Azoles;314
7.2.1;1 Introduction. Azole Antifungal Agents: History, Mode of Action, and Clinical Utility;314
7.2.2;2 Resistance to Azole Antifungal Agents;315
7.2.2.1;2.1 General Considerations and Defi nitions;315
7.2.2.2;2.2 Molecular Mechanisms of Azole Resistance;315
7.2.2.2.1;2.2.1 Alterations in the Target Enzyme;315
7.2.2.2.2;2.2.2 Increased Drug Effl ux;316
7.2.2.2.3;2.2.3 Mutations in other Genes in the Ergosterol Biosynthetic Pathway;316
7.2.2.2.4;2.2.4 Prevalence and Combinations of Molecular Mechanisms of Azole Resistance;316
7.2.2.2.5;2.2.5 Heterogeneity of Molecular Mechanisms of Resistance;316
7.2.2.2.6;2.2.6 Biofi lm Resistance;317
7.2.2.3;3 Genomic and Proteomic Techniques to Study Azole Resistance;317
7.2.2.4;4 Conclusions;317
7.2.2.5;References;318
7.3;Chapter 27 Flucytosine: Site of Action, Mechanism of Resistance and Use in Combination Therapy;320
7.3.1;1 Background;320
7.3.2;2 Mechanism of Action;320
7.3.3;3 5-Flucytosine Resistance;320
7.3.3.1;3.1 Epidemiological Factors Responsible for Resistance;322
7.3.3.2;3.2 Prevention and Control of Resistance;323
7.3.4;4 Mechanism of Resistance;323
7.3.5;5 5-Flucytosine in Combination with Amphotericin B or Fluconazole;324
7.3.5.1;5.1 5-Flucytosine + Amphotericin B;324
7.3.5.1.1;5.1.1 In Vitro Studies;324
7.3.5.1.2;5.1.2 In Vivo Studies;324
7.3.5.1.3;5.1.3 Clinical Studies;326
7.3.5.2;5.2 5-Flucytosine + Fluconazole;326
7.3.5.2.1;5.2.1 In Vitro Studies;326
7.3.5.2.2;5.2.2 In Vivo Studies;327
7.3.5.2.3;5.2.3 Clinical Studies;327
7.3.5.3;5.3 Flucytosine in Combination with Other Triazoles;327
7.3.5.3.1;5.3.1 In Vitro Studies;327
7.3.5.3.2;5.3.2 In Vivo Studies;328
7.3.5.3.3;5.3.3 Clinical Studies;328
7.3.5.4;5.4 Triple Combination: 5-Fluorocytosine + Amphotericin B + Fluconazole;329
7.3.5.4.1;5.4.1 In Vitro Studies;329
7.3.5.4.2;5.4.2 In Vivo Studies;329
7.3.5.4.3;5.4.3 Clinical Studies;329
7.3.6;6 5-Flucytosine in Combination with New Antifungals;330
7.3.7;7 Conclusions;330
7.3.8;References;330
7.4;Chapter 28 Echinocandins: Exploring Susceptibility and Resistance;334
7.4.1;1 Introduction and Background;334
7.4.1.1;1.1 Fungal Cell Walls and 1,3-Beta-D-Glucan Synthesis;334
7.4.1.2;1.2 Inhibitors of GS;335
7.4.1.3;1.3 Echinocandins;335
7.4.1.4;1.4 Antifungal Spectrum of Echinocandins;336
7.4.1.5;1.5 Genetics of 1,3-Beta-D-Glucan Synthase;336
7.4.2;2 Measuring Susceptibility to Echinocandins;337
7.4.2.1;2.1 Yeasts;337
7.4.2.2;2.2 Moulds;338
7.4.3;3 Exploring Resistance in the Laboratory;339
7.4.3.1;3.1 Direct Mutant Selection Using Inhibitors;339
7.4.3.2;3.2 Genetic Screens in S. cerevisiae;341
7.4.3.3;3.3 Genomic Profi ling;342
7.4.3.4;3.4 Proteomics;342
7.4.3.5;3.5 Biochemical Approaches;343
7.4.3.6;3.6 Animal Models;343
7.4.4;4 Potential for Cross-Resistance;345
7.4.5;5 Perspective Beyond the Laboratory;347
7.4.5.1;5.1 Paradoxical Effect;347
7.4.5.2;5.2 Clinical Isolates;348
7.4.6;6 Outlook;348
7.4.7;References;349
7.5;Chapter 29 Antifungal Targets, Mechanisms of Action, and Resistance in Candida albicans;354
7.5.1;1 Introduction;354
7.5.2;2 Ergosterol Biosynthesis Genes and Antifungal Resistance;354
7.5.2.1;2.1 Amphotericin B;362
7.5.2.2;2.2 Regulation of Ergosterol Biosynthesis Genes;363
7.5.2.3;2.3 ERG Gene Overexpression Study;365
7.5.3;3 Effl ux of Antifungals as a Resistance Mechanism;365
7.5.3.1;3.1 ABC Transporters;365
7.5.3.1.1;3.1.1 ABC Pump Inhibitors;370
7.5.3.2;3.2 Regulation of CDR1/CDR2;370
7.5.3.2.1;3.2.1 Regulatory Sequences;370
7.5.3.2.2;3.2.2 Regulatory Proteins: TAC1;370
7.5.3.2.3;3.2.3 Tac1p Regulon;372
7.5.3.2.4;3.2.4 NDT80;373
7.5.3.3;3.3 Drug Effl ux and Membrane Composition;374
7.5.3.4;3.4 Effl ux by Major Facilitators;374
7.5.3.4.1;3.4.1 New Tools for Analysis of Drug Effl ux;375
7.5.4;4 Evidence that Resistance in Clinical Isolates of C. Albicans Is Complex;375
7.5.4.1;4.1 Tolerance Pathways;376
7.5.4.2;4.2 cAMP–Protein Kinase A Pathway;377
7.5.4.3;4.3 Histone Deacetylases as Targets of Azole Adaptive Response;377
7.5.4.4;4.4 Novel Mechanisms for Azole Resistance?;378
7.5.4.4.1;4.4.1 Mitochondrial Respiration and Antifungal Susceptibility;378
7.5.5;5 Hitting Targets outside the Ergosterol Pathway;379
7.5.5.1;5.1 Echinocandins;379
7.5.5.1.1;5.1.1 The Drugs;379
7.5.5.1.2;5.1.2 The Target: FKS1 Encoded b-Glucan Synthetase;380
7.5.5.1.3;5.1.3 Differential Resistance to the Three Echinocandins;382
7.5.5.1.4;5.1.4 Resistance outside FKS1;382
7.5.5.1.5;5.1.5 Global Approaches to Resistance Analysis;383
7.5.5.1.6;5.1.6 Paradoxical Resistance;383
7.5.5.1.7;5.1.7 5-Fluorocytosine and Fluoroorotic Acid;385
7.5.5.2;5.2 Peptides;388
7.5.5.2.1;5.2.1 Histatin;388
7.5.5.2.2;5.2.2 Lactoferrin;389
7.5.5.2.3;5.2.3 Aminoacyl tRNA Synthetase Inhibitors;390
7.5.5.2.4;5.2.4 Sordarins;391
7.5.5.2.5;5.2.5 CAN-296;392
7.5.5.2.6;5.2.6 Steroidal Saponins;392
7.5.5.2.7;5.2.7 Acetominophen;392
7.5.6;6 Resistance in Biofi lms;392
7.5.7;References;395
8;Part V: Viral Drug Resistance - Mechanisms;415
8.1;Chapter 30 Mechanisms of Resistance of Antiviral Drugs Active Against the Human Herpes Viruses;531
8.1.1;1 Introduction;416
8.1.2;2 Thymidine Kinase Herpes Simplex Virus (HSV) Type 1 and Type 2;416
8.1.3;3 HSV DNA Polymerase;417
8.1.4;4 Penciclovir and Famvir;418
8.1.5;5 Human Cytomegalovirus;420
8.1.6;6 Resistance to Ganciclovir;420
8.1.7;7 Maribavir;420
8.1.8;8 CMV DNA Polymerase;421
8.1.9;9 Conclusion;422
8.1.10;References;423
8.2;Chapter 31 Influenza M2 Ion-Channel and Neuraminidase Inhibitors;425
8.2.1;1 Introduction;425
8.2.1.1;1.1 Influenza Viruses;425
8.2.1.2;1.2 Influenza Virus Replication;425
8.2.2;2 M2 Ion-Channel Inhibitors: Amantadine and Rimantadine;425
8.2.2.1;2.1 Antimicrobial Mechanisms of Action;426
8.2.2.1.1;2.1.1 Direct Studies on the Mechanism of Action in Cells;426
8.2.2.1.2;2.1.2 General Structure and Function of the M2 Protein;426
8.2.2.1.3;2.1.3 Structure/Function/Inhibitor Binding to the M2 Protein;427
8.2.2.1.4;2.1.4 Other Effects of Amantadine/Rimantadine on Virus Replication;427
8.2.2.2;2.2 Mechanism of Drug Resistance;427
8.2.2.2.1;2.2.1 Genetics–Mutations Associated with Resistance;427
8.2.2.2.2;2.2.2 Effect of Mutations on Function and Structure of the M2 Ion Channel;428
8.2.2.2.3;2.3 Cross-Resistance;430
8.2.2.2.4;2.4 Mechanism of Spread of Resistance;430
8.2.2.2.5;2.5 Alternative Agents;431
8.2.3;3 Neuraminidase Inhibitors: Zanamivir and Oseltamivir;431
8.2.3.1;3.1 Antimicrobial Mechanisms of Action;432
8.2.3.1.1;3.1.1 Function of the Neuraminidase in Viral Replication;432
8.2.3.1.2;3.1.2 Structure of the Neuraminidase and Enzyme Active Site;432
8.2.3.1.3;3.1.3 Binding of Substrate and Inhibitors to the Active Site;433
8.2.3.2;3.2 Mechanism of Drug Resistance;434
8.2.3.2.1;3.2.1 Development of Resistance to the NAIs;434
8.2.3.2.2;3.2.2 Genetic Analysis of Resistance to the NAIs;435
8.2.3.2.2.1;HA Variants (Mutations Based on H3 Sub-type Numbering);435
8.2.3.2.2.2;NA Variants and Effects of HA Mutations (NA Mutations Numbered Based on the N2 Sub-type Numbering);437
8.2.3.2.2.3;NA Variants Selected During In Vitro Passage or During Treatment in the Clinic;437
8.2.3.2.2.4;Variants Detected in Untreated Subjects During Surveillance Programmes;438
8.2.3.2.2.5;Other NA variants from in vitro studies;438
8.2.3.2.3;3.2.3 Enzyme Functional Studies;439
8.2.3.2.4;3.2.4 Mutant Enzyme Structural Studies;439
8.2.3.3;3.3 Cross-Resistance;440
8.2.3.3.1;3.3.1 Cross-Resistance Analysis with NA Variants Obtained from In Vitro Passage or Clinical Studies with NAIs;440
8.2.3.3.2;3.3.2 Cross-Resistance Analysis Using NA Variants Derived by Reverse Genetics or Recombinants Expressed in HeLa, 293T, or Insect Cells;441
8.2.3.4;3.4 Mechanism of Spread of Resistance;443
8.2.3.5;3.5 Alternative Agents;444
8.2.4;References;445
8.3;Chapter 32 Molecular Mechanisms of Resistance to Nucleoside Reverse Transcriptase Inhibitors;452
8.3.1;1 Introduction;452
8.3.2;2 Nucleoside Reverse Transcriptase Inhibitors;452
8.3.3;3 Resistance Against Nucleoside Analogs;453
8.3.4;4 Mechanisms of Nucleoside Drug Resistance;453
8.3.5;5 Discrimination;454
8.3.5.1;5.1 The M184V/I;455
8.3.5.2;5.2 K65R;455
8.3.5.3;5.3 Q151M;455
8.3.5.4;5.4 L74V;455
8.3.5.5;5.5 V75T;455
8.3.6;6 Excision;456
8.3.7;7 Cross-Resistance and Synergy;457
8.3.8;8 Anti-HIV Drugs that Overcome Resistance;458
8.3.9;References;459
8.4;Chapter 33 Resistance to HIV Non-Nucleoside Reverse Transcriptase Inhibitors;463
8.4.1;1 Introduction: HIV Reverse Transcriptase;463
8.4.2;2 The Non-Nucleoside RT Inhibitors;463
8.4.3;3 Mechanism of NNRTI Drug Resistance;465
8.4.4;4 Mutations Associated with Resistance to NNRTIs;465
8.4.4.1;4.1 Nevirapine Resistance;465
8.4.4.2;4.2 Efavirenz Resistance;466
8.4.4.3;4.3 Delavirdine Resistance;466
8.4.5;5 Cross-Resistance;466
8.4.6;6 Effect of NNRTI Mutations on Enzyme Activity and Viral Replication;468
8.4.7;7 Natural Resistance to NNRTIs;468
8.4.8;8 NNRTIs Hypersusceptibility;469
8.4.9;9 Prevention of Mother-to-Child Transmission;469
8.4.10;10 The Infl uence of Subtype on Resistance Mutation Pathway;469
8.4.11;11 Transmission of NNRTI Resistance;470
8.4.12;12 Structural Determinants of Resistance to NNRTIs;470
8.4.13;13 New NNRTIs in Development;470
8.4.14;14 Conclusion;472
8.4.15;References;472
8.5;Chapter 34 Resistance to HIV-1 Protease Inhibitors;478
8.5.1;1 Mechanism of Action of Protease Inhibitors;478
8.5.1.1;1.1 The HIV-1 Protease;478
8.5.1.2;1.2 HIV-1 PIs;478
8.5.2;2 Mechanism of Drug Resistance;480
8.5.2.1;2.1 Protease Mutations;482
8.5.2.2;2.2 Structural Effects of Mutations;483
8.5.2.3;2.3 Effect of Protease Mutations on Enzyme Activity and Viral Replication;484
8.5.2.4;2.4 Cleavage Site Mutations in PI-Resistant HIV-1;484
8.5.2.5;2.5 Impact of HIV-1 Subtypes and HIV-2 on PI Susceptibility;484
8.5.2.6;2.6 PI Boosting;485
8.5.3;3 Cross-Resistance;485
8.5.4;4 Primary or Transmitted PI Resistance;486
8.5.5;5 Other Pls in Development;486
8.5.6;6 Conclusion;488
8.5.7;References;488
8.6;Chapter 35 Resistance to Enfuvirtide and Other HIV Entry Inhibitors;494
8.6.1;1 Introduction;494
8.6.2;2 Mechanism of Action;495
8.6.2.1;2.1 HIV Interaction with Cellular Receptors;495
8.6.2.2;2.2 The HIV Fusion Process;496
8.6.2.3;2.3 Inhibition of CCR5 Binding;496
8.6.2.4;2.4 Inhibition of the HIV Fusion Process;497
8.6.3;3 Mechanism of Drug Resistance;497
8.6.3.1;3.1 Resistance to CCR5 Binding Inhibitors;497
8.6.3.2;3.2 Resistance to Enfuvirtide;500
8.6.3.3;3.3 The Role of Regions Outside gp41 HR1 in Determining Fusion Inhibitor Susceptibility;501
8.6.3.4;3.4 The Impact of Fusion Inhibitor Resistance Mutations on Viral “Fitness”;502
8.6.3.5;3.5 Interactions Between Entry Inhibitors;502
8.6.4;4 Conclusion;503
8.6.5;References;503
8.7;Chapter 36 Resistance to Inhibitors of Human Immunodefi ciency Virus Type I Integration;508
8.7.1;1 The Role of Integrase in HIV-1 Replication;508
8.7.2;2 Integrase Inhibitor Mechanism of Action;509
8.7.3;3 In Vivo Activity of Integrase Strand Transfer Inhibitors;511
8.7.4;4 Mechanism of Integrase Strand Transfer Inhibitor Resistance and Cross-Resistance: Genetics and Structural Analysis;511
8.7.5;5 Consequences of Resistance;515
8.7.6;6 Alternative Agents;516
8.7.7;References;516
8.8;Chapter 37 The Hepatitis B Virus and Antiviral Drug Resistance: Causes, Patterns, and Mechanisms;519
8.8.1;1 Background and Introduction;519
8.8.2;2 Molecular Virology and Lifecycle;519
8.8.2.1;2.1 Attachment, Penetration, and Uncoating;520
8.8.2.2;2.2 Conversion of Genomic RC DNA into cccDNA and Transcription of the Viral Minichromosome;520
8.8.2.3;2.3 Viral Reverse Transcription;521
8.8.2.4;2.4 Assembly and Release;521
8.8.2.5;2.5 Replication and Diversity of HBV Genomes;522
8.8.3;3 Antiviral Drug Resistance;522
8.8.3.1;3.1 Lamivudine Resistance Mutations (L-Nucleosides);523
8.8.3.2;3.2 Adefovir Dipivoxil Resistance Mutations (Acyclic Phosphonates);524
8.8.3.3;3.3 Entecavir Resistance Mutations (Cyclopenta(e)ne Sugar);525
8.8.3.4;3.4 Multidrug Resistance;525
8.8.4;4 Why HBV Antiviral Drug-Resistant Mutants Are Selected;526
8.8.4.1;4.1 Magnitude and Rate of Virus Replication;526
8.8.4.2;4.2 Fidelity of the Viral Polymerase;526
8.8.4.3;4.3 Selective Pressure of the Drug;527
8.8.4.4;4.4 Amount of Replication Space in the Liver;527
8.8.4.5;4.5 Replication Fitness of the Drug-Resistant Virus;527
8.8.4.6;4.6 Other Factors;527
8.8.5;5 Strategies to Overcome Resistance;527
8.8.6;6 Public Health Implications of the Polymerase Envelope Genes Overlap;528
8.8.7;7 Conclusions;528
8.8.8;References;528
8.9;Chapter 38 Mechanisms of Hepatitis C Virus Drug Resistance;531
8.9.1;1 HCV-Associated Diseases;531
8.9.2;2 Hepatitis C Virus;531
8.9.3;3 Interferon Therapy;531
8.9.4;4 Advances in HCV Treatment;532
8.9.4.1;4.1 Patterns of HCV Response;532
8.9.4.2;4.2 Monotherapy with IFN;532
8.9.4.3;4.3 Combination IFN and Ribavirin Treatment;533
8.9.4.4;4.4 Pegylated-IFN;533
8.9.5;5 Mechanisms of Resistance to Current Therapy;533
8.9.5.1;5.1 HCV Genotype;533
8.9.5.2;5.2 HCV Quasispecies;533
8.9.5.3;5.3 Evasion of Immune Responses;534
8.9.5.4;5.4 Viral Proteins;534
8.9.5.5;5.5 Negative Regulators of Jak/Stat Signaling Pathway;534
8.9.5.6;5.6 Host Negative Regulators of IFN Signaling;535
8.9.6;6 Resistance: In Vitro Models;535
8.9.6.1;6.1 HCV Replicons;535
8.9.6.2;6.2 NS3 Protease Inhibitors;536
8.9.6.3;6.3 HCV Polymerase Inhibitors;537
8.9.6.3.1;6.3.1 Ribavirin;538
8.9.6.3.2;6.3.2 2'-Modifi ed Nucleosides;539
8.9.6.3.3;6.3.3 Non-nucleoside Active-Site Inhibitors;539
8.9.6.3.4;6.3.4 Allosteric Inhibitors Site 1;540
8.9.6.3.5;6.3.5 Allosteric Inhibitors Site 2;540
8.9.7;7 Conclusions and Prospects;541
8.9.8;References;541
9;Part VI: Parasitc Drug Resistance - Mechanisms;546
9.1;Chapter 39 Drug Resistance Mechanisms in Entamoeba histolytica, Giardia lamblia, Trichomonas vaginalis, and Opportunistic Anaerobic Protozoa;547
9.1.1;1 Introduction;547
9.1.2;2 Entamoeba histolytica;549
9.1.2.1;2.1 Antimicrobial Mechanism of Action in E. histolytica;549
9.1.2.2;2.2 Mechanisms of Drug Resistance in E. histolytica;549
9.1.2.2.1;2.2.1 E. histolytica Metronidazole Resistance;549
9.1.2.2.2;2.2.2 Multidrug Resistance in E. histolytica;549
9.1.3;3 Giardia lamblia;550
9.1.3.1;3.1 Antimicrobial Mechanism of Action in G. lamblia;550
9.1.3.2;3.2 Drug Resistance Mechanisms in G. lamblia;551
9.1.3.2.1;3.2.1 Metronidazole Resistance in G. lamblia;551
9.1.3.2.2;3.2.2 Resistance Mechanism to Other Compounds in G. lamblia;551
9.1.3.3;3.3 Cross-Resistance in G. lamblia;551
9.1.4;4 Trichomonas vaginalis;552
9.1.4.1;4.1 Antimicrobial Mechanism of Action in T. vaginalis;552
9.1.4.2;4.2 Drug Resistance Mechanisms in T. vaginalis;552
9.1.4.2.1;4.2.1 Metronidazole Resistance in T. vaginalis;552
9.1.4.2.2;4.2.2 Multiple Drug Resistance in T. vaginalis;552
9.1.4.3;4.3 Cross-Resistance in T. vaginalis;553
9.1.5;5 Other Anaerobic Opportunistic Protozoan Parasites;553
9.1.5.1;5.1 Antimicrobial Treatments Against Opportunistic Protozoan Parasites;553
9.1.5.2;5.2 Drug Resistance in B. hominis, C. parvum, and Microsporidia;553
9.1.6;6 Spread of Resistance in Anaerobic Protozoa;553
9.1.7;7 Alternative Drugs Against E. histolytica, G. lamblia, T. vaginalis, and Opportunistic Protozoa;554
9.1.8;8 Concluding Remarks;554
9.1.9;References;555
9.2;Chapter 40 Mechanisms of Antimalarial Drug Resistance;558
9.2.1;1 Introduction;558
9.2.2;2 Resistance Mechanisms to 4-Aminoquinolines;558
9.2.2.1;2.1 Access to Haematin Is the Biochemical Basis of CQ Resistance;558
9.2.2.2;2.2 pfcrt Is the Genetic Determinant of CQ Resistance;560
9.2.2.3;2.3 Proposed Functional Roles for PfCRT in CQ Resistance;561
9.2.2.4;2.4 pfmdr1 and Resistance Mechanisms to Mefloquine and Quinine;562
9.2.3;3 Resistance Mechanisms to the Antifolates;564
9.2.3.1;3.1 Resistance Caused by Mutations in DHPS and DHFR;564
9.2.3.2;3.2 Further Putative Antifolate Resistance Mechanisms;565
9.2.4;4 Resistance Mechanisms to Naphthoquinones;565
9.2.5;5 Resistance Mechanisms to Artemisinin;566
9.2.6;6 Conclusion;567
9.2.7;References;567
9.3;Chapter 41 Drug Resistance in Leishmania;572
9.3.1;1 Introduction;572
9.3.2;2 Mechanisms of Drug Action and Resistance;574
9.3.2.1;2.1 Antimonials;574
9.3.2.1.1;2.1.1 Mechanisms of Action;574
9.3.2.1.2;2.1.2 Mechanisms of Resistance;576
9.3.2.2;2.2 Amphotericin B;577
9.3.2.2.1;2.2.1 Mechanisms of Action;577
9.3.2.2.2;2.2.2 Mechanisms of Resistance;577
9.3.2.3;2.3 Pentamidine;577
9.3.2.3.1;2.3.1 Mechanisms of Action;577
9.3.2.3.2;2.3.2 Mechanisms of Resistance;578
9.3.2.4;2.4 Alternate Agents;578
9.3.2.4.1;2.4.1 Miltefosine;578
9.3.2.4.1.1;Mechanisms of Action;578
9.3.2.4.1.2;Mechanisms of Resistance;578
9.3.2.4.2;2.4.2 Allopurinol;579
9.3.2.4.3;2.4.3 Atovaquone;579
9.3.2.4.4;2.4.4 Paromomycin;579
9.3.2.4.5;2.4.5 Other Drugs;579
9.3.2.4.5.1;Fluconazole;579
9.3.2.4.5.2;Sitamaquine;579
9.3.2.4.5.3;alpha-Difl uoromethyl Ornithine;580
9.3.2.4.5.4;Antifolates;580
9.3.2.4.5.5;Mechanisms of Action;580
9.3.2.4.5.6;Mechanisms of Resistance;580
9.3.3;3 Spread of Resistance;581
9.3.4;References;581
9.4;Chapter 42 Drug Resistance in African Trypanosomiasis;585
9.4.1;1 Introduction;585
9.4.2;2 Mechanisms of Action of Currently Used Drugs;585
9.4.2.1;2.1 Suramin (Germanin®, Bayer);585
9.4.2.2;2.2 Pentamidine (Pentamidine Isethionate, Aventis);587
9.4.2.3;2.3 Melarsoprol (MelB, Arsobal®, Aventis);587
9.4.2.4;2.4 alpha-Difl uoromethylonithin (DFMO, Efl ornithin, Ornidyl®, Aventis);588
9.4.3;3 Cross-Resistance Analysis;589
9.4.4;4 Mechanisms and Spread of Drug Resistance;591
9.4.4.1;4.1 Origin of Drug Resistance;591
9.4.4.2;4.2 Multiplication of Drug Resistance;592
9.4.4.3;4.3 Dissemination of Drug Resistance;593
9.4.5;5 Experimental Drugs;593
9.4.6;6 New Drug Opportunities;593
9.4.6.1;6.1 Ongoing Developments;594
9.4.6.1.1;6.1.1 Inhibitors of Protein Farnesylation and Myristoylation;594
9.4.6.1.2;6.1.2 Lipid and Fatty Acid Synthesis Inhibitors;594
9.4.6.1.3;6.1.3 Phosphodiesterase Inhibitors;594
9.4.6.1.4;6.1.4 Metabolic Inhibitors;595
9.4.6.1.5;6.1.5 Interference with Protein Glycosylation;595
9.4.6.1.6;6.1.6 New Diamidines;595
9.4.6.2;6.2 ‘Non-rational’ Drug Finding;595
9.4.7;7 Outlook;595
9.4.8;References;596
9.5;Chapter 43 Drug Resistance and Emerging Targets in the Opportunistic Pathogens Toxoplasma gondii and Cryptosporidium parvum;601
9.5.1;1 Toxoplasma gondii: An Opportunistic Pathogen;601
9.5.1.1;1.1 Antimicrobial Mechanism of Action;601
9.5.1.1.1;1.1.1 The Current Treatment of Toxoplasmosis;601
9.5.1.1.2;1.1.2 Is Short-Term Treatment Benefi cial in Congenital and Ocular Toxoplasmosis?;602
9.5.1.2;1.2 Mechanisms of Drug Resistance;602
9.5.1.2.1;1.2.1 Is There Drug Resistance in Toxoplasma?;602
9.5.1.2.2;1.2.2 Drug-Resistant Parasites Are Easily Generated in the Laboratory;603
9.5.1.3;1.3 Why Is There Not More Drug Resistance in the Clinic?;603
9.5.1.4;1.4 Alternative Agents;604
9.5.1.4.1;1.4.1 The Challenge of a Dormant Foe;604
9.5.2;2 Cryptosporidiosis: A Widespread Disease in Developing and Industrialized Countries;604
9.5.2.1;2.1 Antimicrobial Mechanisms of Drug Resistance;604
9.5.2.1.1;2.1.1 What Is the Basis of Cryptosporidium’s Formidable Drug Resistance?;604
9.5.2.1.2;2.1.2 Living on the Edge, C. parvum Is an Intracellular, but Extracytoplasmatic Parasite;605
9.5.2.1.3;2.1.3 Effl ux Pumps Could Contribute to Drug Resistance;606
9.5.2.1.4;2.1.4 C. parvum Is a Highly Divergent Apicomplexan;606
9.5.2.2;2.2 Alternative Agents;607
9.5.2.2.1;2.2.1 The Emerging Genome Sequence Provides an Unprecedented View of C. parvum’s Metabolism;607
9.5.2.2.2;2.2.2 Gene Loss and Horizontal Transfers Shape C. parvum’s Nucleotide Pathway;608
9.5.3;References;609
9.6;Chapter 44 Drug Resistance in Nematodes;616
9.6.1;1 Introduction;616
9.6.2;2 Extent of the Resistance Problem in Nematode Parasites;616
9.6.3;3 Measuring Resistance;618
9.6.4;4 Mechanisms of Resistance;618
9.6.4.1;4.1 Benzimidazoles;618
9.6.4.2;4.2 Levamisole;619
9.6.4.3;4.3 Avermectins and Milbemycins;619
9.6.5;5 Selection for Anthelmintic Resistance;620
9.6.6;6 Management of Nematode Infections in Endemic Regions;621
9.6.7;References;621
9.7;Chapter 45 Chemotherapy and Drug Resistance in Schistosomiasis, Fascioliasis and Tapeworm Infections;624
9.7.1;1 Introduction;624
9.7.1.1;1.1 Schistosomiasis;624
9.7.1.2;1.2 Fasciolosis;625
9.7.1.3;1.3 Cestode (Tapeworm) Infections;625
9.7.2;2 Treatment of Schistosomiasis with Praziquantel;626
9.7.2.1;2.1 History, Chemical Structure and Properties of Praziquantel;626
9.7.2.2;2.2 Effi cacy of Praziquantel;627
9.7.2.3;2.3 Metabolism, Toxicity and Side Effects of Praziquantel;627
9.7.2.4;2.4 Mechanisms of Action of Praziquantel;628
9.7.3;3 Resistance to Praziquantel;628
9.7.3.1;3.1 Evidence of Resistance to Praziquantel in Schistosomes;628
9.7.3.2;3.2 Mechanisms and Markers of Resistance to Praziquantel;629
9.7.4;4 Alternative Agents for Schistosomiasis;630
9.7.4.1;4.1 Oxamniquine;630
9.7.4.1.1;4.1.1 The Activity of Oxamniquine Against S. mansoni;630
9.7.4.1.2;4.1.2 Schistosome Resistance to Oxamniquine;631
9.7.4.2;4.2 Artemisinin Derivatives;631
9.7.4.3;4.3 Ro 15-5458;631
9.7.4.4;4.4 Ro 11-3128;632
9.7.4.5;4.5 Myrrh;632
9.7.5;5 Cross-Resistance and Spread of Resistance to Schistosomicides;632
9.7.5.1;5.1 Refugia;633
9.7.6;6 Drugs for Liver Fluke Infections;633
9.7.6.1;6.1 Triclabendazole;633
9.7.6.2;6.2 Uncouplers;634
9.7.6.3;6.3 Benzimidazoles;634
9.7.6.4;6.4 Clorsulon;634
9.7.7;7 Other Drugs for Tapeworms;634
9.7.7.1;7.1 Pyrantel;634
9.7.7.2;7.2 Benzimidazoles;634
9.7.7.3;7.3 Nitroscanate;634
9.7.7.4;7.4 Niclosamide;634
9.7.7.5;7.5 Treatment of Larval Tapeworms;635
9.7.7.5.1;7.5.1 Taenia solium;635
9.7.7.5.2;7.5.2 Echinococcus granulosus;635
9.7.7.5.3;7.5.3 Echinococcus multilocularis;635
9.7.8;8 Concluding Remarks;635
9.7.9;References;636
9.8;Chapter 46 Drug Resistance in Ectoparasites of Medical and Veterinary Importance;642
9.8.1;1 Introduction;642
9.8.2;2 Background;642
9.8.3;3 Defi nition of Resistance;642
9.8.4;4 Mode of Action and Mechanisms of Resistance;643
9.8.4.1;4.1 The Organophosphates;643
9.8.4.2;4.2 The Carbamates;643
9.8.4.3;4.3 The Pyrethroids;643
9.8.4.4;4.4 The Insect Growth Regulators;643
9.8.4.5;4.5 The Macrocyclic Lactones;643
9.8.4.6;4.6 The Arylheterocycles Phenylpyrazoles;644
9.8.4.7;4.7 The Chloronicotinyl Nitroguanidines;644
9.8.5;5 The Development of Resistance in Individual Genera of Insects;644
9.8.5.1;5.1 Arachnida;644
9.8.5.1.1;5.1.1 Acari (Mites);644
9.8.5.1.2;5.1.2 Ixodida (Ticks);644
9.8.5.2;5.2 Insecta;644
9.8.5.2.1;5.2.1 Diptera (Flies);644
9.8.5.2.2;5.2.2 Ceratopogonidae (Biting Midges);645
9.8.5.2.2.1;Psychodidae–Phlebotominae (Sandfl ies);645
9.8.5.2.2.2;Simuliidae (Blackfl ies);645
9.8.5.2.2.3;Tabanidae (Horsefl ies, Deer Flies and Clegs);645
9.8.5.2.2.4;Glossinidae (Tsetse Flies);645
9.8.5.2.2.5;Muscidae and Fanniidae (Housefl ies and Stablefl ies);645
9.8.5.2.2.6;Calliphoridae (Blowfl ies);645
9.8.5.2.2.7;Oestridae (Gad Flies, Warble Flies and Stomach Bots);646
9.8.5.2.3;5.2.3 Hemiptera (Bugs);646
9.8.5.2.4;5.2.4 Phthiraptera (Lice);646
9.8.5.2.5;5.2.5 Siphonaptera (Fleas);646
9.8.6;6 Cross-Resistance;647
9.8.7;7 Conclusion;647
9.8.8;References;647
10;Index;650