Combating Fungal Infections (eBook)

Preface 6
Editors 10
Contents 14
Contributors 18
Chapter 1: Mould Infections: A Global Threat to Immunocompromised Patients 22
1.1 Introduction 23
1.2 Spectrum of Mould Diseases 24
1.3 Risk Factors for Mould-Disseminated Diseases 25
1.4 Aspergillosis 27
1.5 Zygomycosis 29
1.6 Fusariosis 30
1.7 Scedosporiosis 31
1.8 Other Mould Infections 33
1.8.1 Histoplasmosis and Coccidioidomycosis 33
1.8.2 Emergent and Uncommon Fungi 33
1.9 Future Perspectives and Conclusions 34
References 35
Chapter 2: Virulence and Pathogenicity of Fungal Pathogens with Special Reference to Candida albicans 41
2.1 Introduction 42
2.2 Diseases Caused by Human Pathogenic Fungi 43
2.3 Host-Fungi Interaction: The Process of Infection 44
2.3.1 Entry or Adherence to the Host Tissue 44
2.3.2 Adaptation and Propagation 45
2.3.3 Dissemination 46
2.3.3.1 Host Factors 46
2.3.3.2 Fungal Factors 46
2.4 Virulence and Pathogenicity 47
2.5 Candida albicans: An Opportunistic Fungus 48
2.6 Virulence Factors Involved in Pathogenicity of Candida albicans 51
2.6.1 Adhesion 52
2.6.2 Morphogenesis 52
2.6.3 Phenotypic Switching 53
2.6.4 Phospholipases 54
2.6.5 Proteinases 54
2.6.6 Biofilm Formation 55
2.7 Conclusion 59
References 60
Chapter 3: Animal as Reservoir of Fungal Diseases (Zoonoses?) 66
3.1 Mycoses as Zoonoses 66
3.2 Importance of Molecular Tools in the Study of Fungal Infections 68
3.3 Mycoses 69
3.4 Dermatophytosis 70
3.5 Aspergillosis 72
3.6 Candidiasis 74
3.7 Cryptococcoses 75
3.8 Malassezia pachydermatis 76
3.9 Pneumocystis 77
3.10 Dimorphic Fungi 79
3.10.1 Blastomycosis 79
3.10.2 Histoplasmosis 80
3.10.3 Coccidioidomycoses 81
3.10.4 Sporotrichosis 82
3.11 Pythiosis 83
3.12 Conclusions 83
References 84
Chapter 4: Fungi Associated with Eye Infections with Special Reference to Corneal Keratitis and Their Possible Reservoir 90
4.1 An Introduction to Ocular Fungal Infection 90
4.1.1 Predisposing Risk Factors for Fungal Keratitis 95
4.1.1.1 Corneal Trauma 96
4.1.1.2 Contamination Through Contact Lenses 97
4.1.1.3 Use of Contaminated Topical Steroids 97
4.1.1.4 Other Factors 97
4.2 Infections of the Cornea 98
4.3 Diagnosis of Fungal Infections of the Eye 103
4.3.1 The Detection of Fungal Elements 104
4.3.2 Culture and Identification 104
4.3.3 Molecular Methods for the Diagnosis of Mycotic Keratitis 105
4.4 Soil and Other Environments as Reservoir of Ocular Fungi 107
4.5 Conclusion 111
References 111
Chapter 5: Antifungal Drugs Mode of Action and Recent Development 117
5.1 Antifungal Drugs, Recent Development 117
5.2 Mode of Action 119
5.3 Combination Effect Between Antifungal Agents 121
5.4 Future Developments 124
References 124
Chapter 6: Antifungal-Induced Nephrotoxicity in Pediatrics: A State of the Art 126
6.1 Introduction 127
6.2 Amphotericin B 127
6.2.1 Preterm Babies 128
6.2.2 Newborns and Infants 129
6.3 Amphotericin B Lipid Formulations 129
6.4 Other Antifungals 130
6.4.1 Azoles 130
6.4.1.1 Fluconazole 130
6.4.1.2 Voriconazole 130
6.4.2 Flucytosine 131
6.4.3 Echinocandins 131
6.4.3.1 Caspofungin 132
6.4.3.2 Other Echinocandins 133
6.5 Antifungal Drugs 134
6.5.1 Comparative Data of the Literature 134
6.6 Conclusions 135
References 135
Chapter 7: Antifungal Resistance: Cellular and Molecular Mechanisms 142
7.1 Introduction 142
7.2 Resistance to Polyenes 143
7.2.1 Polyenes for Antifungal Therapy 143
7.2.2 Yeast Resistance to Polyenes 144
7.2.3 Mould Resistance to Polyenes 144
7.3 Resistance to Azoles 145
7.3.1 Azole Antifungal Therapy 145
7.3.2 Yeast Resistance to Azoles 146
7.3.2.1 Gene Expression and Mutations 146
7.3.2.2 Efflux Pumps 147
7.3.2.3 Cellular Stress 148
7.3.3 Mould Resistance to Azoles 149
7.4 Resistance to Echinocandins 150
7.4.1 Echinocandins for Antifungal Therapy 150
7.4.2 Fungal Resistance: Yeast and Moulds 150
7.5 Resistance to Other Antifungals 151
7.5.1 Flucytosine 151
7.5.2 Terbinafine 152
7.6 Resistance in the Environmental Versus in Clinical Isolates 152
7.6.1 Clinical and Epidemiologic Cutoff Values 153
7.7 Future Perspectives and Conclusions 153
References 153
Chapter 8: Multidrug Resistance in Fungi: The Role of Pleiotropic Drug Resistance Genes 163
8.1 Introduction 163
8.2 ABC Transporters 164
8.2.1 Structure and Function 165
8.3 PDR Genes and Role in Drug Resistance 167
8.4 MFS Transporters 174
8.5 Efflux Pumps and Lipid Homeostasis 175
8.5.1 Phospholipid Homeostasis 175
8.5.2 Sphingolipid Homeostasis 176
8.5.3 Sterol Homeostasis 177
8.6 Strategies to Combat Efflux-Mediated Antifungal Resistance 178
References 179
Chapter 9: Laboratory Diagnosis of Fungal Infections: An Overview 188
9.1 Introduction 189
9.2 The Classical Approaches Used in the Laboratory Diagnosis of Fungal Infections 190
9.2.1 Specimen Selection 190
9.2.2 Specimen Collection 190
9.2.3 Specimen Transport and Storage 191
9.2.4 Specimen Processing 191
9.2.5 Fungal Culture 192
9.2.5.1 Media Used for Culture 192
9.2.5.2 Method of Identification of Growth on Culture Media 193
9.2.6 Microscopic Examination 193
9.2.6.1 Direct Method 193
9.2.6.2 Other Staining Methods 195
9.3 Role of Serological Tests in Laboratory Diagnosis of Fungal Infections 196
9.4 Molecular Approaches in the Laboratory Diagnosis of Fungal Infections 196
9.5 The Laboratory Identification of Fungal Isolates 197
9.5.1 Laboratory Identification of Yeasts and Yeast-Like Organisms 197
9.5.1.1 Media Used for Identification 197
Cornmeal Agar 197
CHROMagar 198
Bird Seed Agar/Niger Seed Agar 198
Germ Tube Test 198
9.5.1.2 Biochemical Tests for Identification 199
Rapid Urease Test 199
Carbohydrate Utilization Tests 199
9.5.1.3 Serodiagnosis for Identification 200
Detection of Antigen 200
Detection of Antibodies 200
9.5.1.4 Detection of Fungal Metabolites for Identification 200
9.5.1.5 Molecular Techniques for Identification 201
9.5.2 Laboratory Identification of Dermatophytes 201
9.5.2.1 Primary Media for Identification of Dermatophytes 202
Mycosel/Mycobiotic Agar 202
Sabouraud´s Dextrose Agar with Antibiotics 202
Dermatophyte Test Medium (DTM) 202
Dermatophyte Identification Medium (DIM) 206
9.5.2.2 Specific Media for Identification of Dermatophytes 206
Potato Dextrose Agar 206
Rice Medium 206
Casamino Acids/Erythritol/Albumin Medium 206
Bromocresol Purple (BCP)/Casein Yeast Extract Agar 206
Bromocresol Milk Solids Glucose Agar 206
Trichophyton Agars 1-7 206
Sporulation-Stimulating Media 207
9.5.2.3 Tests for Identification of Dermatophytes 207
In Vitro Hair Perforation Test 207
Urease Test 207
Test for Temperature Tolerance and High-Temperature Enhancement of Growth 208
9.5.2.4 Trichophytin Skin Test (Immunodiagnosis) for Dermatophytes 208
9.5.2.5 Molecular Techniques for Dermatophytes 208
9.5.3 Laboratory Identification of the Dimorphic Fungi 208
9.5.3.1 Microscopic Examination of Dimorphic Fungi 209
9.5.3.2 Media Used for Identification of Dimorphic Fungi 209
9.5.3.3 Tests for Identification of Dimorphic Fungi 212
Exoantigen Test 212
Direct Fluorescent Antibody Test (DFA) 212
Indirect Fluorescent Antibody Test 212
Skin Tests 212
9.5.3.4 Serodiagnosis for Dimorphic Fungi 213
Blastomyces Dermatitidis 213
Histoplasma Capsulatum 213
Coccidioidis Immitis 214
Paracoccidioides Brasiliensis 214
Penicillium Marneffei 214
9.5.3.5 Molecular Techniques for Dimorphic Fungi 215
9.5.4 Laboratory Identification of Aspergillus Species 215
9.5.4.1 Media Used for Identification of Aspergillus Species 216
Czapek Agar 216
Potato Dextrose Agar 216
9.5.4.2 Skin Test for Identification of Aspergillus Species 216
9.5.4.3 Serodiagnosis of Aspergillus Species 216
Tests for Antibodies 216
Tests for Antigens 218
9.6 Laboratory Safety Considerations 218
References 219
Chapter 10: Combinational Antifungal Therapy and Recent Trends in Drug Discovery 227
10.1 Introduction 228
10.2 Combinational Antifungal Therapy 229
10.2.1 Principle of Combinational Therapy 230
10.2.2 In Vitro Antifungal Drug Interactions 231
10.2.3 In Vivo Antifungal Drug Interactions and Clinical Trials 234
10.3 New Strategy for Antifungal Drug Discovery 236
10.3.1 Targeting Virulence and Pathogenicity 236
10.3.2 Use of Genomic Approaches in Antifungal Drug Discovery 239
10.3.2.1 Principle of Genomic-Based Antifungal Drug Discovery 240
10.3.2.2 Identification and Validation of New Antifungal Targets 241
10.3.3 Progress in the Genomic Approach to Antifungal Drug Discovery 242
10.4 Conclusion 246
References 247
Chapter 11: Role of De-Escalation and Combination Therapy Strategies in the Management of Invasive Fungal Infection: A Multidi. 255
11.1 Introduction 256
11.2 Systemic Antifungal Agents Today 256
11.3 Antifungal Administration Routes 257
11.3.1 Intravenous (IV) Route 257
11.3.2 Oral Route 269
11.3.3 Inhalation Route 269
11.4 Treatment of Invasive Candidiasis in ICU Patients and De-Escalation Therapy 270
11.5 Combination Therapy 270
11.5.1 ICU Patients 270
11.5.2 Hematological Patients 272
11.5.3 Solid Organ Transplant Recipients 273
11.5.3.1 Lung Transplantation 274
11.5.3.2 Non-Pulmonary Solid Organ Transplantation 275
11.6 Conclusion 281
References 282
Chapter 12: Challenges to the Management of Pulmonary Mycoses in Allogeneic Hematopoietic Stem Cell Transplantation 287
12.1 Introduction 287
12.1.1 Spectrum of Fungal Pathogens 288
12.1.2 Pathogenesis and Risk Factors of Pulmonary Mycoses Following Allogeneic HSCT 288
12.1.3 Prevention of IFI Following Allogeneic HSCT 289
12.2 Diagnosis of Pulmonary Mycosis 291
12.3 Antifungal Agents Used in the Treatment of IFI in Allogeneic HSCT 292
12.4 Respiratory Support 295
12.5 Conclusions 295
References 297
Chapter 13: Aspartic Peptidase Inhibitors as Potential Bioactive Pharmacological Compounds Against Human Fungal Pathogens 302
13.1 Introduction 302
13.2 Proteolytic Enzymes and Proteolytic Inhibitors 303
13.2.1 Aspartic-Type Peptidases 308
13.3 Aspartic Peptidases of Human Pathogenic Fungi: A New Target for Fungal Drug Development 311
13.3.1 Candida spp 311
13.3.2 Other Pathogenic Fungi 317
13.4 Aspartic Peptidase Inhibitors: A Novel Alternative for Fungal Treatment? 317
13.4.1 Candida albicans 322
13.4.2 Cryptococcus neoformans 324
13.4.3 Fonsecaea pedrosoi 327
13.4.4 Sporothrix schenckii 328
13.4.5 Histoplasma capsulatum 329
13.5 Conclusions 329
References 330
Chapter 14: Metabolic Pathways as Drug Targets: Targeting the Sulphur Assimilatory Pathways of Yeast and Fungi for Novel Drug . 339
14.1 Introduction 339
14.2 The Sulphur Assimilatory Pathway of Humans is Distinct from Fungi: A Potential for Drug Discovery 341
14.3 The Sulphur Assimilatory Pathways of the Yeast Saccharomyces cerevisiae and Other Model Yeast and Fungi 342
14.4 Studies on the Sulphur Assimilatory Pathways in the Pathogenic Yeasts/Fungi 344
14.4.1 Candida glabrata and Candida albicans 346
14.4.2 Histoplasma capsulatum 347
14.4.3 Paracocciodiodes brasiliensis 347
14.4.4 Dermatophytes (Trichophyton, Microsporum, and Epidermophton) 347
14.4.5 Cryptococcus neoformans 348
14.5 Metabolic Targets in the Sulphur Assimilatory Pathway 349
14.5.1 Homoserine O-Acetyl Transacetylase (MET2) 349
14.5.2 Methionine Synthase (MET6) 349
14.5.3 ATP Sulphurylase (MET3) 350
14.5.4 Homoserine Dehydrogenase HOM6 351
14.5.5 Transcription Factor Protein (MET4) 351
14.5.6 Sulphite Transporter 352
14.5.7 Cystine Transporter 352
14.5.8 Glutathione Utilization Pathway and Glutathione Biosynthesis Pathway 352
14.6 Concluding Remarks 353
References 354
Chapter 15: Innate Immunity in Pathogenesis and Treatment of Dermatomycosis 359
15.1 Introduction 360
15.2 Dermatomycosis: An Increasing Problem 361
15.2.1 Epidermophyton spp. 361
15.2.2 Microsporum spp. 361
15.2.3 Trichophyton spp. 361
15.2.4 Infections 362
15.2.4.1 Tinea barbae 362
15.2.4.2 Tinea faciei 364
15.2.4.3 Tinea capitis 364
15.2.4.4 Tinea corporis 364
15.2.4.5 Tinea cruris (Jock Itch) 364
15.2.4.6 Tinea favosa 365
15.2.4.7 Tinea imbricata 365
15.2.4.8 Tinea manuum 365
15.2.4.9 Tinea pedis (Athlete´s Foot) 365
15.2.4.10 Tinea ungium 365
15.3 Fungal Infections and Immunity 366
15.4 Therapy of Fungal Infection and Immune Response 367
15.5 Skin and Innate Immunity 368
15.5.1 Stratum corneum 369
15.6 Pathogenesis and Innate Immunity 369
15.7 Treatment 372
15.8 TLR and Dermatomycosis 376
15.8.1 The TLR and Functions of the Innate Immune System 376
15.8.1.1 Sensory Functions 376
15.8.1.2 Effector Functions 377
15.9 Conclusion 377
References 378
Chapter 16: Cytokine Therapy: Possible Tools in Management of Fungal Infection 384
16.1 Introduction 385
16.2 Immune System in Fungal Infections 385
16.3 Role of Cytokine in Regulation of Immune Cells in Fungal Infections 386
16.3.1 Lymphocytes 386
16.3.2 Neutrophils 387
16.3.3 Dendritic Cells 388
16.4 Role of Cytokines in Treating IFIs 389
16.4.1 Immunomodulatory Role of Cytokine 389
16.4.2 Therapeutic Role of Cytokines 390
16.4.2.1 IFN-gamma 391
16.4.2.2 The CSFs 392
Granulocyte Colony-Stimulating Factor 392
Granulocyte-Macrophage Colony-Stimulating Factor 393
Macrophage Colony-Stimulating Factor 394
16.4.2.3 TNF-a 394
16.4.2.4 RANTES 395
16.5 Which Patients Are Likely to Respond to Cytokine Therapy? 395
16.6 Mechanisms for Synergy Between Antifungal Therapy and Immune Responses 399
16.7 Conclusions and Future Prospects 400
References 402
Chapter 17: Immunomodulators: Potential in Treatment of Systemic Fungal Infections 408
17.1 Introduction 409
17.2 Immunomodulators 410
17.3 Combinational Trends of Antifungals with Immunomodulators 411
17.4 Tuftsin: A Highly Effective Immunomodulator 413
17.5 Cytokines as Nonspecific Immunomodulators 415
17.5.1 Hematopoietic Growth Factors (HGF) 416
17.5.2 Anti-inflammatory Cytokines 417
17.5.3 Pro-inflammatory Cytokines 418
17.5.4 Cytokine Therapy in Neutropenic Hosts 418
17.5.5 Recombinant Cytokines 420
17.6 Plant Components as Immunomodulatory Agents 420
17.7 Monoclonal Antibody-Based Immunomodulator 422
17.8 Immune Peptides as Immunomodulators 422
17.9 Conclusion 423
References 424
Chapter 18: Fungal Vaccines: Recent Trends 433
18.1 Fungal Vaccine 434
18.1.1 Prolonged Antibacterial Therapy 434
18.1.2 Increased Number of AIDS Cases 435
18.1.3 Increased Use of Corticosteroids 435
18.1.4 More Aggressive Treatment Modalities of Cancer Patients, Particularly Those with Leukemia and Lymphoma 435
18.1.5 Increased Number of Bone Marrow Transplant and Solid Organ Transplant Procedures 435
18.1.6 Catheter-Borne Infections Among Patients 435
18.1.7 Intravenous Drug Abuse 436
18.1.8 Increased Use of Surgical Procedures 436
18.1.9 The Success of Intensive Care Units in Prolonging the Survival of Highly Immunocompromised Patients 436
18.2 Historical Perspective 437
18.3 Goals of Immunization (Deepe 1997) 437
18.4 Requirements for a Successful Immunization Program 438
18.5 Mechanisms of Protection 438
18.5.1 Innate Immunity 438
18.5.2 Acquired Immunity 439
18.5.2.1 Cellular Immunity (T-Cell Mediated Immunity) 439
18.5.2.2 Humoral Immunity 441
18.6 Fungal Immunogens 442
18.6.1 Blastomyces dermititidis 442
18.6.1.1 Immunogens 442
18.6.1.2 Vaccine 443
18.6.2 Candida albicans 444
18.6.2.1 Immunogens 444
18.6.2.2 Vaccines 444
18.6.3 Coccidioides immitis 446
18.6.3.1 Immunogens 446
18.6.3.2 Vaccines 446
18.6.4 Cryptococcus neoformans 446
18.6.4.1 Immunogens 446
18.6.4.2 Vaccines 447
18.6.5 Histoplasma capsulatum 447
18.6.5.1 Immunogens 447
18.6.5.2 Vaccines 447
18.7 Paracoccidioides brasiliensis 448
18.7.1 Immunogens 448
18.7.2 Vaccines 448
18.8 Pneumocystis carinii (or P. jirovecii) 448
18.9 Penicillium marneffei 449
18.9.1 Immunogen 449
18.9.2 Vaccine 449
18.10 Approaches to Vaccination 449
18.10.1 Conventional Methods 449
18.10.2 Adjuvants 450
18.10.2.1 Cytokines as Adjuvants 450
18.10.3 DNA Vaccine 450
18.10.4 Dendritic Cell Vaccination 451
18.10.5 Altered Fungus (Crippled Fungus) as Vaccine 451
18.11 Therapeutic Vaccination 451
18.12 Vaccination of the Immunocompromised Host 452
References 452
Chapter 19: Antifungal Activity of Medicinal Plant Extracts and Phytocompounds: A Review 459
19.1 Introduction 460
19.2 Screening of the Crude Extracts and Antifungal Activity 461
19.3 Classes of Compounds and Their Antifungal Activity 464
19.3.1 Terpenoids 464
19.3.2 Saponins 472
19.3.3 Phenolic Compounds 473
19.3.3.1 Flavones, Flavonoids, and Flavonols 475
19.3.3.2 Coumarins 476
19.3.4 Alkaloids 477
19.3.5 Proteins and Peptides 479
19.4 Experimental Approaches 479
19.4.1 Selection of Plants 479
19.4.2 Scheme for the Extraction and Identification of Active Principle 480
19.4.3 Solvent for Testing 482
19.4.4 Antifungal Assays 482
19.4.4.1 Agar Well Diffusion Method 482
19.4.4.2 Broth Dilution Method 483
19.4.4.3 TLC-Bioautography Technique 484
19.4.4.4 Media, Inoculum and Organisms 484
19.5 Conclusion 485
References 485
Chapter 20: Novel Drug Delivery Systems for Antifungal Compounds 495
20.1 Introduction 496
20.2 Liposomes 498
20.2.1 Liposomes as Drug-Delivery Vehicles 500
20.2.2 Specialized Liposomes (Long-Circulating Liposomes) 501
20.2.2.1 GM1 and Glucoronide Liposomes 502
20.2.2.2 PEG-Coated Liposomes (Stealth Liposomes) 503
20.2.2.3 Targeted Liposomes/Immmunoliposomes 504
20.2.2.4 pH-Sensitive Liposomes 506
20.2.3 Liposomal Formulations 506
20.3 Nanoparticles (Polymer-Drug Conjugates) 510
20.3.1 Nanoparticle Formulations 513
20.4 Micelles (Amphiphilic Block Copolymers) 514
20.4.1 Formulations Based on Micelles 516
20.5 Cyclodextrins 516
20.5.1 Cyclodextrin (CD) Formulations 518
20.6 Cochleate Lipid Cylinders 519
20.6.1 Antifungal Formulations of Cochleates 520
20.7 Niosomes 521
20.8 Microspheres 523
20.9 Conclusion 524
References 525
Index 539