Antimicrobial Drug Resistance (eBook)

Preface 5
Table of Contents Antimicrobial Drug Resistance Volume 2 6
Contributors 13
Section G: Gram - Positive Bacterial Drug Resostance - Clinical 25
Chapter 47 Resistance in Streptococcus pneumoniae 26
1 Introduction 26
2 Epidemiology of the Pneumococcus and Risk Factors for Resistance 26
3 The Role of Clones in Resistance 27
4 Laboratory Detection of Resistance 28
5 Resistance to Beta-Lactams 28
6 Resistance to Macrolides 29
7 Resistance to Fluoroquinolones 30
8 Resistance to New Classes of Antibiotics 31
9 Resistance to Other Agents 31
10 Clinical Relevance of Antibiotic Resistance 32
11 Impact of Conjugate Vaccine 32
12 Concluding Remarks 33
References 33
Chapter 48 Antibiotic Resistance of Non-Pneumococcal Streptococci and Its Clinical Impact 39
1 Characteristics of Non-pneumococcal Streptococci 39
1.1 Viridans Streptococci 39
1.2 Beta-Hemolytic Streptococci 39
1.3 Group A Streptococcus (Streptococcus pyogenes) 39
1.4 Group B Streptococcus (Streptococcus agalactiae) 40
1.5 Groups C and G Beta-Hemolytic Streptococci 40
2 Antimicrobial Resistance in VGS 40
2.1 Beta-Lactam Resistance 40
2.2 Resistance to Macrolides, Lincosamides and Ketolides 42
2.3 Erythromycin Resistance 42
2.4 Clindamycin Resistance 42
2.5 Ketolide Resistance 44
2.6 Streptogramin Resistance 44
2.7 Tetracycline and Trimethoprim-Sulfamethoxazole Resistance 44
2.8 Fluoroquinolone Resistance 44
2.9 Activity of Glycopeptides and Aminoclycosides 44
2.10 Activity of Linezolid 46
3 Antimicrobial Resistance in Beta-Hemolytic Streptococci 46
3.1 Resistance to Macrolides 46
3.1.1 Incidence of Macrolide Resistance in GAS 46
3.1.2 Incidence of Macrolide Resistance in GBS 46
3.1.3 Incidence of Macrolide Resistance in GCG and GGS 47
3.1.4 Mechanisms of Macrolide Resistance in Beta-Hemolytic Streptococci 47
3.1.5 Epidemiology of Macrolide-Resistant Beta-Haemolytic Streptococci 48
3.2 Resistance to Clindamycin 49
3.3 Resistance to Telithromycin 49
3.4 Resistance to Tetracycline 49
4 Clinical Significance of Resistance 49
4.1 Infections Caused by VGS 49
4.1.1 Infective Endocarditis 49
4.1.2 Septic Infections Due to VGS in Neutropenic Patients 50
4.2 Beta-Hemolytic Streptococci 51
References 52
Chapter 49 Enterococcus: Antimicrobial Resistance in Enterococci Epidemiology, Treatment, and Control 59
1 General Description 59
1.1 Microbiology 59
1.2 Epidemiology 59
1.3 Clinical Manifestations 60
1.4 Laboratory Diagnosis 60
1.5 Pathogenesis 60
2 Susceptibility In Vitro and In Vivo 60
2.1 Aminoglycoside Resistance in Enterococci 60
2.2 Penicillin Resistance 61
2.3 Glycopeptide Resistance 61
3 Antimicrobial Therapy 61
3.1 Urinary Tract Infections 62
3.2 Intraabdominal Infections 62
3.3 Endocarditis 63
3.4 Meningitis 64
3.5 Therapy for Strains Resistant to Aminoglycosides 64
3.6 Therapy for Strains Resistant to Penicillins and Glycopeptides, but Susceptible to Aminoglycosides 64
3.7 Therapy for Strains Resistant to Penicillins, Glycopeptides, and Aminoglycosides 65
4 Adjunctive Therapy 68
5 Endpoints for Monitoring Therapy 68
6 Vaccines 68
7 Infection Control 68
8 Summary and Conclusions 70
References 71
Chapter 50 Antimicrobial Resistance in Staphylococci: Mechanisms of Resistance and Clinical Implications 78
1 Introduction 78
2 Resistance to Specifi c Antimicrobial Agents 78
2.1 Natural Penicillins 78
2.2 Methicillin and Other Beta-Lactams 79
2.3 Vancomycin 80
2.4 Macrolides, Lincosamides, and Streptogramins 80
2.5 Aminoglycosides 81
2.6 Trimethoprim–Sulfamethoxazole 81
2.7 Tetracyclines 81
2.8 Fluoroquinolones 81
2.9 Rifampin 82
2.10 Linezolid 82
2.11 Daptomycin 82
2.12 Small Colony Variants 82
3 Epidemiology of Antimicrobial Resistance 82
4 Clinical Implications of Antimicrobial Resistance 83
4.1 Initial Therapy: S. aureus 83
4.2 Defi nitive Therapy: MSSA 83
4.3 Defi nitive Therapy: MRSA 84
4.4 Combination Therapy 85
4.5 Use of Fluoroquinolones 85
4.6 Vancomycin Resistance 85
4.7 Coagulase-Negative Staphylococci 86
5 Conclusions 86
References 86
Chapter 51 Resistance in Aerobic Gram-Positive Bacilli 92
1 Overview 92
1.1 Microbiology 92
1.2 Clinical Syndromes 92
1.2.1 Bacillus anthracis Infection 92
1.2.2 Bacillus cereus Food Poisoning 94
1.2.3 Opportunistic Bacillus Species Infections 94
2 Therapy of Bacillus Infections 95
2.1 Infections due to Bacillus anthracis 95
2.1.1 In Vitro Antibiotic Susceptibility 95
2.1.2 Antimicrobial Resistance in Bacillus anthracis 95
2.1.3 Recommended Therapy 96
2.1.4 Recommended Prophylaxis Following Inhalation Exposure 97
2.1.5 Adverse Events Following Anthrax Postexposure Prophylaxis and Therapy 97
2.2 Infections due to Bacillus Species Other than B. anthracis 97
2.2.1 In Vitro Antibiotic Susceptibility 97
2.2.2 Antimicrobial Resistance 98
2.2.3 Recommended Therapy 98
3 Germicide Susceptibility of Bacillus spp. 98
4 Infection Control 98
5 Conclusions 98
References 99
Section H: Gram - Negative Bacterial Drug Resistance - Clinical 103
Chapter 52 Antibiotic Resistance in Neisseria 104
1 Introduction 104
2 Neisseria gonorrhoeae 104
2.1 Overview of Gonococcal Disease 104
2.1.1 Worldwide Distribution 104
2.1.2 Clinical Manifestations 105
2.1.3 Treatment and Control Strategies 105
2.2 Antibiotic Resistance in N. gonorrhoeae 105
2.2.1 Development and Spread of Antibiotic Resistance in N. gonorrhoeae 106
Resistance to Penicillins (Penicillin, Ampicillin, Amoxicillin, Penicillin/Beta-lactamase Inhibitor Combinations) 106
Cephalosporin Antibiotics 107
Quinolone Antibiotics 107
Spectinomycin 107
Tetracyclines 108
Sulfonamide–Trimethoprim Combinations 108
Newer Macrolides 108
Aminoglycosides 109
Chloramphenicol/Thiamphenicol 109
2.2.2 Laboratory Determination of Resistance 109
Agar Dilution (Agar Incorporation) Methods 109
Disc Diffusion Methods 109
E-Test 109
Comparability of MIC Data 109
Detection of Beta-Lactamase (Identifi cation of PPNG) 109
Special Test Requirements for Some Antibiotics 109
DNA Probe and Hybridization Techniques for Susceptibility Determination 110
2.3 Clinical Signifi cance of Resistance in N. gonorrhoeae 110
2.3.1 Epidemiology 110
2.3.2 Surveillance 110
Country-Based Data 111
2.4 Treatment 111
2.4.1 Management of N. gonorrhoeae Infections 111
2.4.2 Current Antibiotic Recommendations 112
Cephalosporins 112
Quinolones 112
Spectinomycin 112
Suboptimal or Obsolete Treatments 112
2.4.3 Infection Control Measures 113
3 Neisseria meningitidis 113
3.1 Overview of Meningococcal Disease 113
3.1.1 Epidemiology and Clinical Manifestations 113
3.1.2 Treatment and Control 114
3.2 Antimicrobial Resistance in N. meningitidis 115
3.2.1 Penicillins 115
3.2.2 Chloramphenicol 116
3.2.3 N. Meningitidis Resistance to Agents Used for Prophylaxis 116
3.3 Clinical Signifi cance of Resistance in N. meningitidis 116
3.4 Treatment and Infection Control Recommendations 117
4 Commensal Neisseria Species 117
References 118
Chapter 53 Mechanisms of Resistance in Haemophilus infl uenzae and Moraxella catarrhalis 124
1 Overview 124
2 Carriage of H. infl uenzae and M. catarrhalis 124
3 Major Diseases Caused by H. infl uenzae and M. catarrhalis 124
3.1 Meningitis 124
3.2 Childhood Pneumonia and Bacteremia 125
3.3 Community-Acquired Pneumonia in Adults 125
3.4 Acute Otitis Media 126
3.5 Acute Sinusitis 126
3.6 Acute Exacerbations of Chronic Bronchitis 126
4 Baseline Susceptibility and Development of Resistance 127
5 Mechanisms of Resistance of H. infl uenzae and M. catarrhalis 127
5.1 Beta-Lactams 127
5.2 Protein Synthesis Inhibitors 129
5.3 MLS Agents and Ketolides 129
5.4 Tetracyclines 130
5.5 Quinolones 130
5.6 Chloramphenicol 130
5.7 Folic Acid Metabolism Inhibitors 130
6 History of Geographical Spread 131
6.1 Haemophilus influenzae 131
6.2 Moraxella catarrhalis 131
7 Clinical Signifi cance 132
8 Laboratory Determination of Susceptibility 138
8.1 MIC Determination 138
8.2 Disk Diffusion Testing 138
8.3 Gradient Diffusion (E-test) 139
8.4 Beta-Lactamase Detection 139
9 Infection Control Measures 139
10 Conclusions 139
References 139
Chapter 54 Enterobacteriaceae 143
1 Overview of Resistance Trends 143
2 ESBL-Producing Enterobacteriaceae 144
2.1 General Issues and Nomenclature 144
2.2 In Vitro Susceptibility Profiles and Clinical Outcomes 144
2.3 Treatment of ESBL Producers 144
2.4 Community-Acquired ESBLs 145
3 Antibiotic Resistance in Enterobacter Species 146
4 Emerging Quinolone and Carbapenem Resistance 146
4.1 Quinolone Resistance 146
4.2 Carbapenem Resistance 147
5 Conclusions 147
References 147
Chapter 55 Pseudomonas aeruginosa 151
1 Microbiology 151
2 Habitats of P. aeruginosa 151
3 Pulmonary Infections with P. aeruginosa 151
4 Bloodstream Infections with P. aeruginosa 152
5 Other Serious Infections with P. aeruginosa 152
6 Less Serious Infections with P. aeruginosa 152
7 Mechanisms of Resistance of P. aeruginosa to Antimicrobial Agents 152
8 Epidemiology of Infections Due to Multidrug Resistant P. aeruginosa 153
8.1 Treatment of Serious Infections with P. aeruginosa 153
8.1.1 Combination Therapy for P. aeruginosa 154
8.1.2 Optimizing Therapy Aimed at P. aeruginosa 154
9 Conclusions 155
References 155
Chapter 56 Acinetobacter 158
1 Overview 158
2 History of Geographical Spread 158
3 Epidemiology 159
4 Clinical Signifi cance 159
5 Laboratory Diagnosis of Resistance 159
6 Treatment Alternatives 160
7 Infection Control Measures 161
References 161
Chapter 57 Antimicrobial Resistance of Shigella spp., Typhoid Salmonella and Nontyphoid Salmonella 163
1 Introduction 163
2 Importance of Shigella and Salmonella 163
2.1 Shigella 163
2.2 Typhoid Salmonella 163
2.3 Nontyphoid Salmonella 164
3 Patterns of Susceptibility of Shigella spp. by Geography 164
4 Enteric Fever Due to Strains of Salmonella Typhi and S. Paratyphoid 164
5 Gastroenteritis Due to Nontyphoid Salmonella 165
6 Current Therapeutic Recommendations 166
6.1 Shigella 166
6.2 Typhoid Fever 167
6.3 Nontyphoid Salmonellosis 167
References 168
Chapter 58 Antimicrobial Resistance in Vibrios 171
1 Introduction 171
2 Cholera Caused by V. cholerae O1 or O139 172
2.1 Geographic Spread and Epidemiology of Resistance 172
2.2 Clinical Signifi cance 175
2.3 Laboratory Diagnosis of Resistance 176
2.4 Treatment Alternatives 176
2.5 Infection Control Measures 177
3 Disease Caused by Vibrios Other than V. cholerae O1 or O139 177
3.1 Geographic Spread and Epidemiology of Resistance 177
3.2 Clinical Signifi cance 178
3.3 Laboratory Diagnosis of Resistance 178
3.4 Treatment Alternatives 178
3.5 Infection Control Measures 178
References 179
Chapter 59 Antimicrobial Resistance in Helicobacter and Campylobacter 184
1 Introduction 184
2 Helicobacter pylori 184
2.1 In Vitro Antimicrobial Susceptibility Testing and Interpretive Criteria for H. pylori 185
2.2 Clinical Signifi cance of Resistance 186
2.3 Resistance to Specifi c Antimicrobials 186
2.3.1 Beta-Lactam Resistance 186
2.3.2 Fluoroquinolone Resistance 186
2.3.3 Macrolide Resistance 186
2.3.4 Nitrofuran Resistance 187
2.3.5 Nitroimidazole Resistance 187
2.3.6 Rifamycin Resistance 187
2.3.7 Tetracycline Resistance 187
3 Campylobacter jejuni/coli 188
3.1 In Vitro Antimicrobial Susceptibility Testing and Interpretive Criteria 189
3.2 Clinical Signifi cance of Resistance 190
3.3 Resistance to Specifi c Antimicrobials 190
3.3.1 Macrolides 190
3.3.2 Quinolones 191
3.3.3 Tetracycline 191
3.3.4 Aminoglycosides 192
3.3.5 Other Resistances 192
References 192
Chapter 60 Pertussis (Whooping Cough) 201
1 Overview and Bacteriology 201
2 History of Geographic Spread 201
3 Epidemiology 202
4 Clinical Signifi cance 202
5 Laboratory Diagnosis 203
5.1 Specimen Collection and Transport 203
5.2 Direct Detection 203
5.3 Culture 204
5.4 In Vitro Antimicrobial Susceptibility Testing 204
5.5 Serology 204
6 Alternative Treatments 205
7 Infection Control and Prevention Measures 205
8 Summary 206
References 206
Chapter 61 Antibiotic Resistance of Anaerobic Bacteria 208
1 Infections Caused by Anaerobic Bacteria 208
2 Susceptibility Patterns of Anaerobic Bacteria 209
3 Susceptibility Testing and Their Interpretation 209
4 Resistance Mechanisms of Anaerobic Bacteria 211
4.1 Clindamycin Resistance 211
4.2 Beta-lactam Resistance 213
4.2.1 Production of beta-Lactamase 214
4.2.2 Penicillin Binding Proteins 215
4.2.3 Permeability 215
4.3 Metronidazole (5-Nitroimidazoles) Resistance 215
4.4 Fluoroquinolones Resistance 216
4.5 Aminoglycosides Resistance 216
4.6 Chloramphenicol Resistance 217
4.7 Tetracycline Resistance 217
5 Transfer of Antibiotic Resistance 217
6 The Role of beta-Lactamase-Producing-Bacteria in Mixed Infections 218
6.1 Mixed Infections Involving Anaerobic BLPB 219
6.2 Production of BL by AGNB in Clinical Infections 220
6.3 Evidence for Indirect Pathogenicity of Anaerobic BLPB 221
6.3.1 In Vivo and In Vitro Studies 221
6.3.2 BL in Clinical Infections 221
6.3.3 Clinical Studies Illustrating Failure of Penicillins Due to Anaerobic BLPB 222
6.4 Therapeutic Implications of Indirect Pathogenicity 223
7 Antimicrobial Therapy of Anaerobic Infections 224
7.1 Antimicrobial Therapy 224
7.2 Antimicrobial Agents 225
7.2.1 Penicillins 225
7.2.2 Cephalosporins 226
7.2.3 Carbapenems (Imipenem, Meropenem, Doripenem, Ertapenem) 226
7.2.4 Chloramphenicol 227
7.2.5 Clindamycin and Lincomycin 227
7.2.6 Metronidazole 227
7.2.7 Macrolides (Erythromycin, Azithromycin, Clarithromycin) 227
7.2.8 Glycopeptides (Vancomycin, Teicoplanin) 227
7.2.9 Tetracyclines (Tetracycline, Doxycycline, Minocycline) 227
7.2.10 Glycylcyclines 227
7.2.11 Floroquinolones 227
7.2.12 Other Agents 228
7.3 Choice of Antimicrobial Agents 228
References 228
Chapter 62 Mycobacteria: Tuberculosis 235
1 Overview 235
2 Epidemiology 235
3 Laboratory Diagnosis of Resistance 237
3.1 First-Line Drugs Susceptibility Testing 237
3.1.1 Conventional Methods 237
3.1.2 Other Methods 239
Molecular Assays 239
3.2 Second-Line Susceptibility Testing 239
4 Clinical Signifi cance and Treatment 240
4.1 Drug Sensitive Tuberculosis 240
4.2 Drug Resistant Tuberculosis 241
4.2.1 Low- and Middle-Income Countries 242
4.2.2 Exrapulmonary Drug Resistant TB 243
4.3 Global Policy for MDRTB Therapy 243
4.4 HIV and MDRTB 243
4.5 Therapeutic Alternatives: Immunotherapy 243
4.6 Surgical Management 244
4.7 Economic Value of Treating MDRTB 245
4.8 Infection Control Measures 245
References 245
Chapter 63 Drug Resistance by Non-Tuberculous Mycobacteria 250
1 Introduction 250
2 Clinical Presentations 250
2.1 Skin and Soft Tissue Infections 250
2.2 Lymphadenitis 250
2.3 Medical Device and Nosocomial NTM Infections 250
2.4 Pulmonary Disease 251
2.5 Disseminated Disease 251
3 Therapy 251
3.1 Drug Regimens 251
3.2 Susceptibility Testing 251
3.3 Treatment Outcomes and Prognosis 253
3.4 Adjunctive Therapies 253
3.5 Emerging Antimicrobials 254
3.6 Drug Toxicities and Intolerances 254
4 Prophylaxis and Prevention 255
5 Mechanisms of Resistance 255
5.1 Primary and Acquired Resistance Associated with Genetic Alterations of Drug Targets 255
5. 2 Morphotypic Antibiotic Resistance of MAC 255
5.3 Intrinsic Drug Resistance 257
6 Concluding Remarks 257
References 257
Section I: Fungal Drug Resistance - Clinical 261
Chapter 64 The Role of Resistance in Candida Infections: Epidemiology and Treatment 262
1 Introduction 262
2 Epidemiology of Candidiasis 262
3 Mechanism of Action of Antifungal Drugs (See Reviews) (34, 35) 263
3.1 Polyenes 263
3.2 Fluoropyrimidines 263
3.3 Azoles 263
3.4 Echinocandins 263
4 Defi nition of Resistance 263
4.1 Refractory Candidiasis 263
4.2 Primary or Secondary Resistance 264
5 Antifungal Susceptibility Tests 264
5.1 Methods 264
5.2 In vitro Susceptibility and Resistance of Candida Species 265
5.2.1 Azoles 265
5.2.2 Flucytosine 266
5.2.3 Polyenes 266
5.2.4 Echinocandins 267
5.3 Correlation of in vitro Susceptibility Testing and Clinical Outcome of Treatment with Antifungal Agents 267
5.4 Indications for Antifungal Susceptibility Testing in Candida Infections 268
6 Pathogenesis of Resistant Candidiasis - Risk Factors 268
6.1 HIV/AIDS 268
6.2 Hematologic Malignancies and Transplant Patients 269
6.3 Prosthetic Devices/in vivo Biofi lm 269
6.4 Antifungal Drugs 269
6.5 Candida vaginitis 270
6.6 Azole Cross-Resistance 270
6.7 Drug Pharmacokinetics, Pharmacodynamics and Resistance in Candidiasis 271
7 Refractory Candidiasis: Clinical Resistance Syndromes and Their Management 271
7.1 Oropharyngeal and Esophageal Candidiasis 271
7.1.1 Treatment 272
Refractory Oropharyngeal Candidiasis 272
Refractory Esophageal Candidiasis 272
7.2 Refractory Candida vaginitis (VVC) 273
7.3 Refractory Candidemia and Disseminated Candidiasis 274
7.3.1 C. albicans 274
7.3.2 C. glabrata 275
8 Adjuvant Therapy for Resistant Candidiasis 275
9 Prevention of Antifungal Resistance in Candida Species 275
10 Conclusion and Perspective 276
References 276
Chapter 65 Antifungal Resistance: Aspergillus 283
1 Introduction 283
2 In Vitro Resistance 283
2.1 Known Mechanisms of Resistance 283
2.2 Resistance to Polyenes 284
2.3 Resistance to Triazoles 286
2.4 Resistance to Echinocandins 288
2.5 Resistance to Allylamines 289
3 Animal Models 289
4 Clinical Data: Resistance 290
4.1 Resistance to Polyenes 290
4.2 Resistance to Azoles 291
4.3 Resistance to Echinocandins 291
5 Conclusion 292
References 293
Chapter 66 Drug Resistance in Cryptococcus neoformans 296
1 Introduction 296
2 Definitions 296
2.1 Clinical Resistance 297
2.1.1 Clinical Resistance Patterns in Patients Without HIV Infection 297
2.1.2 Clinical Resistance Patterns in Patients With HIV Infection 297
2.1.3 Clinical Resistance and Pharmacologic Limitations 297
2.1.4 Cryptococcal Virulence Factors and Clinical Resistance 298
3 Susceptibility Testing 298
3.1 Modifi cations to the M27-A2 Document 298
3.2 The E-Test for Antifungal Susceptibility Testing 299
3.3 Interpretive Breakpoints 299
3.4 Clinical Relevance of In Vitro Fungal Susceptibility 299
4 Epidemiology of Cryptococcal Antifungal Drug Resistance 300
5 Antifungal Drugs and Molecular Mechanisms of Resistance 301
5.1 Polyenes 301
5.2 Fluoropyrimidines 302
5.3 Azoles 303
5.3.1 Sterol Biosynthesis 303
5.3.2 14a-Demethylase (ERG11) 304
5.3.3 Multi-Drug Efflux Pumps 304
5.3.4 Heteroresistance 304
5.4 Glucan Synthesis Inhibitors 305
6 Strategies to Overcome Drug Resistance in Cryptococcus neoformans 306
6.1 Primary Prophylaxis 306
6.2 Host Immune Function Modulation 306
6.2.1 Cytokine Therapy 306
6.2.2 Antibody Therapy 307
6.3 Pharmacotherapeutic Strategies 307
6.3.1 Drug Dosing 307
6.3.2 Drug Selection 307
6.4 Combination Therapy 308
6.4.1 Amphotericin B Plus Flucytosine 308
6.4.2 Fluconazole Plus Flucytosine 308
6.4.3 Other Combinations 308
6.5 Surgical Intervention 308
6.6 New Drug Targets and Drug Development 309
6.6.1 Benzimidazole Compounds 309
6.6.2 Immunophilins and the Inhibition of Signal Transduction Pathways 309
6.6.3 ATPase Activity and H+ Transport 309
6.6.4 Sordarins 310
6.6.5 Novel Drug Combinations 310
7 Conclusions 310
References 310
Chapter 67 Antifungal Drug Resistance in Histoplasmosis 315
1 Introduction 315
2 Treatment 315
2.1 Amphotericin B 315
2.2 Itraconazole 316
2.3 Fluconazole 316
2.4 New Agents 316
2.5 Combination Therapy 316
3 Resistance 317
3.1 Susceptibility Testing 317
3.2 Resistance as a Cause for Failure 317
3.3 Mechanisms of Antifungal Resistance 318
4 Conclusion 319
References 319
Chapter 68 Drug Resistance in Pneumocystis jirovecii 321
1 Introduction 321
2 The Organism 321
3 Transmission and Infection 322
4 Drug Treatment 322
5 Prophylaxis 323
6 Treatment of PCP 324
7 Sulfonamide Resistance 327
8 DHFR Resistance 329
8.1 Atovaquone 331
9 Pentamidine and Clindamycine–Primaquine 331
10 Conclusion 331
References 331
Section J: Viral Drug Resistance - Clinical 336
Chapter 69 Antiviral Resistance in Infl uenza Viruses: Clinical and Epidemiological Aspects 337
1 Introduction 337
2 M2 Ion Channel Inhibitors (Amantadine, Rimantadine) 338
2.1 Detection of Resistance 338
2.2 Susceptibility of Field Isolates 338
2.2.1 Swine and Avian Viruses 339
2.2.2 A(H5N1) Viruses 340
2.3 Resistance in Posttreatment Isolates 340
2.3.1 Immunocompetent Patients 340
2.3.2 Immunocompromised Hosts 341
2.4 Transmissibility of Resistant Variants 341
2.4.1 Households 341
2.4.2 Chronic Care Facilities 342
2.5 Pathogenicity 342
2.6 Treatment Alternatives 343
3 Neuraminidase Inhibitors (Zanamivir, Oseltamivir) 344
3.1 Detection of Resistance 344
3.2 Susceptibility of Field Isolates 345
3.2.1 Surveillance Studies to 2006 345
3.2.2 A(H1N1) Viruses 346
3.2.3 A(H5N1) Viruses 347
3.2.4 HA Mutations 347
3.3 Resistance in Posttreatment Isolates 347
3.3.1 Immunocompetent Hosts 347
3.3.2 Immunocompromised Hosts 349
3.4 Transmissibility of Resistant Variants 349
3.5 Pathogenicity 350
3.6 Treatment Alternatives 351
4 Modeling Studies 352
5 Implications and Future Research Directions 352
5.1 Current Clinical Use of Antivirals 353
5.2 Future Research Directions 353
References 353
Chapter 70 Herpesvirus Resistance 360
1 Antiviral Agents for Herpesvirus Infections 360
2 Human Cytomegalovirus Resistance 361
2.1 Phenotypic and Genotypic Assays to Evaluate HCMV Drug Susceptibility 361
2.2 Clinical Significance, Incidence, and Risk Factors for Drug-Resistant HCMV Infections 362
2.3 Role of HCMV UL97 and UL54 Mutations in Drug-Resistant Clinical Strains 363
2.4 When and How to Monitor for HCMV Resistance 364
2.5 Management of Infections Caused by Resistant HCMV Strains 365
3 Herpes Simplex Virus and Varicella-Zoster Virus Resistance 365
3.1 Phenotypic and Genotypic Assays to Evaluate HSV and VZV Drug Susceptibility 365
3.2 Clinical Significance, Incidence, and Risk Factors for Drug-Resistant HSV and VZV Infections 366
3.3 Management of Infections Caused by Resistant HSV and VZV Strains 367
4 Conclusions 367
References 368
Chapter 71 Clinical Implications of HIV-1 Drug Resistance 373
1 Overview 373
2 Epidemiology 373
3 Prevalence 374
4 Transmission 374
5 Prevention of Mother-to-Child Transmission 375
6 Clinical Signifi cance 376
7 Resistance to HIV Nucleotide Reverse Transcriptase Inhibitors 376
8 Resistance to HIV-1 Non-nucleoside Reverse Transcriptase Inhibitors 376
9 Resistance to HIV-1 Protease Inhibitors 376
10 Resistance to HIV-1 Entry Inhibitors 377
11 Resistance to HIV Integrase Inhibitors 377
12 Mutational Interactions 377
13 Viral Fitness (Replication Capacity) 377
14 Clades 378
15 Laboratory Diagnosis of HIV-1 Drug Resistance 378
16 Treatment of Drug-Resistant HIV-1 379
16.1 Initial Treatment of HIV-1 379
16.2 Treatment of Drug-Resistant HIV-1 380
16.3 Salvage Therapy for Drug-Resistant HIV-1 380
16.4 Novel Classes of Antiretroviral Drugs 380
16.5 Prevention of HIV-1 Drug Resistance 380
References 381
Chapter 72 Clinical Implications of Resistance for Patients with Chronic Hepatitis B 385
1 Scientifi c Background, Natural History, and Treatment Goals in Chronic Hepatitis B: Similarities and Contrasts with HIV Infection 385
2 Contrasts in Natural History and Treatment Goals for Patients with Chronic HBV Infection vs. HIV Infection 385
3 Implications for Viral Resistance (HBV vs. HIV) 387
4 Current Antiviral Treatment Optionsfor Hepatitis B Patients and Associated Resistance Observations 388
4.1 Lamivudine Resistance 389
4.2 Adefovir Resistance 390
4.3 Entecavir Resistance 391
4.4 Telbivudine Resistance 391
5 Cross-Resistance Issues for Current Anti-HBV Agents 392
6 Optimizing Antiviral Therapy for Hepatitis B Patients: Potential Treatment Strategies for Minimizing the Clinical Impact of Antiviral Resistance 393
References 395
Section K: Parasitic Drug Resistance - Clincal 398
Chapter 73 Antimalarial Drug Resistance: Clinical Perspectives 399
1 Introduction 399
2 The Current Malaria Situation 399
3 History of Antimalarial Therapy and Currently Available Drugs 399
4 History, Mechanisms, and Current Epidemiology of Antimalarial Drug Resistance 401
5 Evaluation of Antimalarial Drug Resistance 404
5.1 Clinical Assessment of Drug Resistance 404
5.2 Requirements for Clinical Drug Efficacy Studies 405
5.3 Interpretation of Results of Clinical Drug Efficacy Studies 407
5.4 In vtro Assessment of Antimalarial Drug Efficacy 407
5.5 Molecular Assessment of Antimalarial Drug Resistance 408
6 New Directions in Assessment of Antimalarial Drug Resistance 409
7 New Directions in Antimalarial Chemotherapy 409
References 410
Chapter 74 Diagnosis and Treatment of Metronidazole-Resistant Trichomonas vaginalis Infection 413
1 Trichomonas vaginalis 413
2 Epidemiology 413
2.1 Prevalence and Transmission 413
2.2 Association with Human Immunodeficiency Virus and Other STDs 414
3 Clinical Aspects 414
3.1 Trichomoniasis in Men 414
3.2 Trichomoniasis in Women 414
3.3 Diagnosis 415
3.4 Treatment 416
4 Metronidazole Resistance 417
4.1 Mechanisms 417
4.2 Diagnosis of Resistance 418
4.3 Treatment 418
5 Alternative Treatments 418
6 Infection Prevention 419
References 419
Chapter 75 Drug Resistance in Leishmania: Clinical Perspectives 423
1 Overview 423
2 Epidemiology 423
3 Treatment of Leishmaniasis and Drug Resistance 425
3.1 History of Geographical Spread of Resistance 425
3.2 Clinical Signifi cance of and Epidemiological Reasons for Drug Resistance 426
3.3 Laboratory Diagnosis of Resistance 427
3.4 Mechanism of Drug Resistance 428
3.5 Treatment Alternatives 428
3.5.1 Combination Therapy 430
3.6 Infection Control Measures 430
References 431
Chapter 76 Human African Trypanosomiasis 435
1 Overview 435
2 Geographic Spread 437
3 Risk Factors for Treatment Failures 437
4 Pharmacokinetics and Laboratory Diagnosis of Resistance 438
5 Mechanisms of Resistance 439
6 Treatment Alternatives 440
7 Disease Control 440
References 440
Chapter 77 Drug Resistance in Toxoplasma gondii 442
1 Overview 442
2 History, Epidemiology and Clinical Significance of Drug Resistant T. gondii 443
3 Laboratory Diagnosis of Drug ResistantIn fections 444
4 Treatment Alternatives 444
5 Infection Control Measures 445
References 446
Chapter 78 Drug Resistance in the Sheep Nematode Parasite Haemonchus contortus, Mechanisms and Clinical Perspectives 448
1 Overview 448
2 History of Geographical Spread 449
3 Epidemiology 449
4 Clinical Signifi cance 450
5 Laboratory Diagnosis 450
6 Treatment Alternatives and Infection Control Measures 451
References 452
Section L: Measurements of Drug Resistance 454
Chapter 79 In Vitro Performance and Analysis of Combination Anti-infective Evaluations 455
1 Introduction 455
2 Methods 456
2.1 Defi nition of the Dose–Response Curve and Selectivity Index for the Drugs Evaluated 456
2.2 Analysis of the Interaction of the Drugs Used in Combination 457
2.2.1 Multiple Dose–Response Curves 458
2.2.2 Isobolograms 458
2.2.3 Combination Index Method 459
2.2.4 Three-Dimensional Surface Analysis 460
2.2.5 Parametric Surface Fitting 460
2.3 Additional Considerations in Design of Combination Drug Evaluations 460
2.3.1 Combination Effi cacy and Combination Toxicity 460
2.3.2 Mutually Exclusive and Mutually Nonexclusive Evaluations 461
2.3.3 Performance and Evaluation of Three-Drug Combination Assays 462
2.3.4 Combination Testing with Resistant Organisms 462
2.3.5 Combination Resistance Selection Evaluations 462
2.3.6 Combination Assays to Evaluate Treatment for Multiple Infectious Organisms 463
2.4 Special Case: Potentiation and Suppression 463
2.4.1 Biological Relevance of the Test System to the Therapeutic Strategy 463
2.4.2 In Vitro Pharmacologic Models and Evaluations 464
3 Virologic Evaluations 464
3.1 Virus Replication and Functional Cell-Based Assays 464
3.2 Assays Measuring Cytopathic Effects 464
3.3 Enzymatic and Biochemical Assays 465
3.4 Chronic and Acute Infection Assays 465
4 Microbiologic Evaluations 465
4.1 Methods to Study Antibiotic Interactions 465
4.1.1 Checkerboard Testing 465
4.1.2 Time-Kill Testing 466
4.1.3 E-Test Strip 466
4.2 Combination Testing and Prediction of Clinical Outcome 466
References 467
Chapter 80 Antimicrobial Susceptibility Testing Methods for Bacterial Pathogens 470
1 Introduction 470
2 Antimicrobial Susceptibility Testing Methods 470
2.1 Disk Diffusion 470
2.2 Minimal Inhibitory Concentration Testing 471
2.2.1 Agar Dilution 471
2.2.2 Broth Microdilution 472
2.2.3 Automated Susceptibility Testing Methods 472
2.2.4 Agar Gradient Dilution 472
3 Interpretive Guidelines 472
4 Resistance Phenotypes that Require Specialized Testing 473
4.1 beta-Lactam Agents 473
4.2 Macrolides, Azalides, Lincosamides, and Streptogramins 474
4.3 Aminoglycosides 474
4.4 Sulfa Drugs and Trimethoprim 474
4.5 Glycopeptides 474
4.6 Fluoroquinolones 475
4.7 Oxazolidinones 475
5 Molecular Tests to Detect Resistant Bacteria 475
5.1 General Considerations 475
5.2 Assays for MRSA and Vancomycin- Resistant Enterococcus (VRE) 475
6 Conclusions 476
References 476
Chapter 81 Drug Resistance Assays for Mycobacterium tuberculosis 479
1 Drug Resistant Tuberculosis as a Public Health Problem 479
2 Defi nitions and Terminologyin the Field of Tuberculosis 480
2.1 Drug-Resistant Strain 480
2.2 Critical Concentrations 480
2.3 Direct and Indirect Drug Susceptibility Tests 480
2.4 Primary (Initial) Drug Resistance 481
2.5 Acquired Drug Resistance 481
2.6 Multidrug Resistance 481
2.7 Poly-resistance 481
2.8 First-Line Drugs 481
2.9 Second-Line Drugs 481
3 Empiric Approach for Detecting Patients with Drug Resistance 481
4 Drug Susceptibility Tests Using Egg-Based Culture Medium 481
5 Agar Proportion Method 482
6 Drug Susceptibility Testing (Indirect Test) in Liquid Medium 483
7 Molecular Phenotypic and Genotypic Methods 484
References 486
Chapter 82 Fungal Drug Resistance Assays 489
1 The Need for Fungal Drug Resistance Assays 489
1.1 Theoretical Limitations on the Correlation of In Vitro Susceptibility with Clinical Outcome 489
2 The Currently Used Reference and Alternative Fungal Drug Resistance Assays 490
2.1 CLSI Reference Broth Dilution Methods 490
2.1.1 Current Status and Limitations of the CLSI Broth Dilution Methods 490
Amphotericin B Susceptibility Tests 490
MIC Breakpoints for the Determination of the Susceptibility Category 492
Time Required to Finalize the Fungal Resistance Tests 492
2.2 EUCAST Reference Broth Dilution Method 493
2.3 CLSI Disk Diffusion Method 493
2.4 Colorimetric Broth Dilution Methods 494
2.5 Etest 495
2.6 Agar Dilution Method 496
2.7 Determination of Fungicidal Activity 496
2.8 Other Methods: Fully Automated Systems, Flow Cytometry, and Sterol Quantitation 497
3 Indications for Use of Fungal Drug Resistance Assays 498
4 In Vitro Antifungal Combination Studies 498
5 Keywords and Conclusions 498
References 498
Chapter 83 Viral Phenotypic Resistance Assays 505
1 Introduction 505
2 Intact Virus Susceptibility Assays 505
2.1 Plaque Assays 505
2.2 Virus Yield or Antigen Expression Assays 505
2.3 Limitations of Intact Virus Assays 506
3 Phenotypic Drug Susceptibility Assays for HIV-1 506
3.1 Plaque Reduction Assays 506
3.2 Peripheral Blood Mononuclear Cell-Based Assays 506
3.3 Recombinant Virus Assays 507
3.3.1 Phenotype Test Interpretation 508
3.3.2 Adaptation of Recombinant Virus Assays to Entry Inhibitors 509
3.4 Assays for HIV Fitness and Replication Capacity 509
3.5 Determining Co-Receptor Tropism for HIV-1 510
3.5.1 MT-2 Assays 511
3.5.2 Recombinant Viral Assays for Tropism 511
3.5.3 Comparison of MT-2 and Recombinant Virus Coreceptor Tropism Assays 511
4 Phenotypic Drug Susceptibility Assays for Hepatitis B Virus 511
5 Phenotypic Drug Susceptibility Assays for Hepatitis C Virus 512
6 Phenotypic Drug Susceptibility Assays for Herpesviruses (HSV, CMV, VZV) 512
7 Phenotypic Drug Susceptibility Assays for Infl uenza Virus 513
References 513
Chapter 84 Drug Resistance Assays for Parasites 518
1 Introduction 518
1.1 Establishment, Development and Dispersal of Resistance 518
1.2 Sensitivity, Specifi city and Level of Resistance 518
1.3 Challenges 519
1.4 Mechanisms of Resistance 519
2 Assay Methods to Detect Resistance 519
2.1 In Vivo Bioassays 519
2.1.1 In Vivo in Defi nitive Host 519
2.1.2 In Vivo in Experimental Hosts 519
2.2 In Vitro Assays 519
2.2.1 Survival (Effect) Assays 519
2.2.2 Phenotypic Assay 526
2.2.3 Genetic Assay 526
2.3 Sampling 526
2.4 Analysis of Data 527
2.4.1 General 527
2.4.2 Analysis 527
2.5 Artefacts 528
3 Parasites 528
3.1 Plasmodium 528
3.1.1 In Vivo 528
3.1.2 Survival: In Vitro 528
3.1.3 Genetic 529
3.1.4 Specimen Collection 529
3.1.5 Practical Tests, Clinical Signifi cance and Breakpoints 529
3.1.6 Artefacts 529
3.2 Eimeria 529
3.3 Trypanosoma (Ruminants) 530
3.3.1 In Vivo 530
3.3.2 In Vivo (Experimental Animals) 530
3.3.3 Survival: In Vitro 530
3.3.4 Phenotypic Assay 530
3.3.5 Genetic 530
3.3.6 Specimen Collection 531
3.3.7 Practical Tests, Clinical Signifi cance and Breakpoints 531
3.4 Trypanosoma (Humans) 531
3.5 Leishmania 531
3.5.1 In Vivo (Experimental Animal) 531
3.5.2 Survival: In Vitro 532
Promastigotes 532
Amastigote-Macrophage Models 532
Axenic Amastigote Systems 532
3.6 Giardia, Trichomonas and Entamoeba 532
3.6.1 In Vivo 532
3.6.2 In Vitro 533
3.6.3 Phenotypic Assays 533
3.6.4 Genetic 533
3.6.5 Specimen Collection 533
3.6.6 Practical Tests, Clinical Signifi cance and Breakpoints 534
3.6.7 Artefacts 534
3.7 Trichostrongyloids 534
3.7.1 In Vivo 534
3.7.2 In Vivo (Experimental Animal) 535
3.7.3 In Vitro 535
3.7.4 Genetic 536
3.7.5 Specimen Collection 536
3.7.6 Practical Tests, Clinical Signifi cance and Breakpoints 537
3.7.7 Artefacts 537
3.8 Fasciola 537
3.9 Schistosoma 537
4 Conclusions 538
References 538
Chapter 85 Genotypic Drug Resistance Assays 543
1 Introduction 543
2 Mechanisms of Resistance to Antimicrobial Agents 543
2.1 Resistance to Aminoglycosides 544
2.2 Resistance to b-Lactams 544
2.3 Resistance to Glycopeptides 544
2.4 Resistance to Macrolides, Lincosamides, and Streptogramins 544
2.5 Resistance to Quinolones 544
2.6 Resistance to Trimethoprim– Sulfamethoxazole 545
2.7 Resistance to Tetracyclines 545
2.8 Resistance to Chloramphenicol 545
2.9 Resistance to Linezolid 545
2.10 Resistance to Rifampin 545
2.11 Resistance to Isoniazid 545
2.12 Resistance to Ethambutol 545
2.13 Resistance to Pyrazinamide 545
3 Methods to Detect Resistance 546
3.1 Phenotypic Assays/Susceptibility Tests (Culture) 546
3.2 Special Phenotypic Susceptibility Methods 546
3.2.1 Detection of Oxacillin Resistance in Staphylococci 546
3.2.2 Detection of Vancomycin Resistance in Enterococci and Staphylococci 547
3.2.3 Detection of Enzyme-Mediated Resistance 547
3.2.4 Clinical Signifi cance of Breakpoints 547
3.3 Genotypic Assays 548
3.3.1 Genotypic Detection of Drug-Resistant Mycobacterium tuberculosis 549
3.3.2 Genotypic Detection of Oxacillin Resistance in Staphylococci 551
3.3.3 Genotypic Detection of Glycopeptide Resistance in Enterococci and Staphylcocci 552
3.3.4 Potential Artifacts of Genotypic Resistance Testing 553
4 The Future of Genotypic Drug Resistance Detection 553
References 554
Chapter 86 The Use of Genotypic Assays for Monitoring the Development of Resistance to Antiviral Therapy for HIV-1 Infection and Other Chronic Viral Diseases 565
1 Introduction 565
2 Genotypic Drug Resistance in HIV-1 Infection 566
3 Nucleoside Analog Reverse Transcriptase Inhibitors 566
4 Non-nucleoside Reverse Transcriptase Inhibitors 568
5 Protease Inhibitors 569
6 Fusion Inhibitors (Enfuvirtide, T-20) 569
7 Limitations of Genotype Resistant Testing for Treatment of Infection with HIV-1 570
8 Hepatitis B Infection 570
9 Herpes Virus Infections: Cytomegalovirus and Herpes Simplex Virus 572
10 Future Perspectives 574
References 575
Section M: Public Health Issues of Drug Resistance 581
Chapter 87 Antimicrobial Resistance: An International Public Health Problem 582
1 Introduction 582
2 Public Health as a Perspectiveon Resistance (10) 582
2.1 Morbidity and Mortality 583
2.2 Added Healthcare Costs 583
3 Contrasts Between the Public Health View of Resistance and Other Views 584
3.1 Physicians 584
3.2 Patients 585
3.3 Healthcare Businesses 585
3.4 Industry 585
3.5 Summary: A Dramatic Difference in Viewpoints 585
4 Infl uences on Resistance and Control Strategies 585
4.1 Providers 586
4.2 Local Health Departments and Hospitals 587
4.3 Regional, National, and International Health Organizations 587
5 Public Health Perspectives of Antimicrobial Resistance According to Resource Limitation Levels (10) 587
5.1 Settings with Extensive Resources 587
5.2 Settings with Minimal Resources 588
5.3 Settings with Signifi cant Resource Limitation 588
5.4 Settings with Minimal to Moderate Resources 589
6 Conclusion: Antimicrobial Resistancein the Era of Globalization: An International Concern for Public Health 589
References 589
Chapter 88 Hospital Infection Control: Considerations for the Management and Control of Drug-Resistant Organisms 592
1 Introduction 592
2 The Importance of Patient and Healthcare Worker Colonization with Drug-Resistant Pathogens: Reservoirs for Infection 592
3 The Impact of Colonization Status on Nosocomial Infections 594
4 The Role of Mupirocin for S. aureus Nasal Carriage Decolonization 595
5 Environmental Contamination 596
6 Hand Hygiene 598
7 The Use of Gloves and Gowns to Limit Cross-Transmission of Nosocomial Pathogens 599
8 Gowns 599
9 Transmission-Based Precautions 600
9.1 Airborne Precautions 600
9.2 Droplet Precautions 600
9.3 Contact Precautions 601
10 Measures to Control Nosocomial Outbreak of Drug-Resistant Pathogens 601
11 Screening for Asymptomatic Patient Colonization with Drug-Resistant Pathogens 601
12 Antibiotic Control Programs and Surveillance for Nosocomial Infections 602
13 Conclusion 603
References 604
Chapter 89 Controlling the Spread of Resistant Pathogens in the Intensive Care Unit 609
1 Overview 609
2 Reservoirs 609
2.1 Fecal and Cutaneous Flora 610
2.2 The Inanimate Environment 610
3 Major Infectious Disease Syndromes Commonly Encountered in the ICU 610
3.1 Device-Associated Bacteremia 610
3.2 Ventilator-Associated Pneumonia 611
3.3 Sepsis in Immunosuppressed Patients in the ICU 612
4 Resistant Pathogens of Particular Interest to ICU Staff 612
4.1 Methicillin-Resistant Staphylococcus aureus 612
4.2 Vancomycin-Resistant Enterococcus 613
4.3 Resurgent C. diffi cile Enterocolitis 614
4.4 Multiply Resistant A. baumannii 614
5 Measures to Prevent and Control Infection in the ICU 615
5.1 General Infection Control Measures 615
5.2 Syndrome-Specifi c Infection Control Measures 624
5.2.1 Preventing Device-Associated Bacteremia in the ICU 624
5.2.2 Preventing ICU-AssociatedVentilator-Associated Pneumonia 625
5.2.3 Preventing Infection in ImmunocompromisedPatients in the ICU 625
References 625
Chapter 90 Implications of Antibiotic Resistance in Potential Agents of Bioterrorism 629
1 Introduction 629
1.1 Defi nitions 629
2 Threat Agents 629
3 Bioterrorism Preparedness and Response 630
3.1 Laboratory Response Network 630
3.2 Epidemiological Investigations 631
4 Critical Bacterial Agents 632
4.1 Detection of Resistance 632
4.1.1 Genomic Analysis for Determination of Possible Intrinsic Resistance 633
4.2 Bacillus anthracis 634
4.2.1 General Characteristics 634
4.2.2 Antimicrobial Susceptibility and Resistance 634
4.3 Yersinia pestis 638
4.3.1 General Characteristics 638
4.3.2 Antimicrobial Susceptibility and Resistance 639
4.4 Francisella Tularensis 641
4.4.1 General Characteristics 641
4.4.2 Antimicrobial Susceptibility and Resistance 641
4.5 Burkholderia pseudomallei 643
4.5.1 General Characteristics 643
4.5.2 Antimicrobial Susceptibility and Resistance 643
4.6 Burkholderia mallei 643
4.6.1 General Characteristics 643
4.6.2 Antimicrobial Susceptibility and Resistance 643
4.7 Brucella spp. 644
4.7.1 General Characteristics 644
4.7.2 Antimicrobial Susceptibility and Resistance 645
4.8 Coxiella burnetii 646
4.8.1 General Characteristics 646
4.8.2 Antimicrobial Susceptibilities and Resistance 647
Methodology 647
Intrinsic Resistance 647
Engineered Resistance 647
5 Conclusions and Future Considerations 648
References 648
Chapter 91 Internet Resources on Antimicrobial Resistance 653
1 Signifi cance of Internet Resources on Antimicrobial Resistance 653
2 Methodology of WWW Resource Selection 654
3 Internet Resources on Antimicrobial Resistance from Major International Networks 654
4 Internet Resources on Antimicrobial Resistance from Major National Networks 654
5 Internet Links on Antimicrobial Resistance from Major Networks 654
6 Limitations in the Selection of Relevant Internet Resources 654
7 Conclusion 658
References 658
Index 660