Fundamental Medical Mycology Fundamental Medical Mycology Errol Reiss Mycotic Diseases Branch, Centers for Disease Control and Prevention, Atlanta, Georgia H. Jean Shadomy Department of Microbiology and Immunology, Virginia Commonwealth University, School of Medicine, Richmond, Virginia G. Marshall Lyon, III Department of Medicine, Division of Infectious Diseases, Emory University, School of Medicine, Atlanta, Georgia A JOHN WILEY & SONS, INC., PUBLICATION ThisbookwaswrittenbyErrolReissinhisprivatecapacity.NoofficialsupportorendorsementbytheCentersforDiseaseControlandPrevention, DepartmentofHealthandHumanServicesisintended,norshouldbeinferred. 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Contents Preface xvii 1.6.2 InvestigatingOutbreaks 10 1.6.3 Determining the Susceptibilityto Acknowledgments xix AntifungalAgents 10 1.6.4 Estimating theSignificance of Fungi Generally Considered to be Opportunists or Saprobes 10 1.6.5 Types of VegetativeGrowth 10 Part One Introduction to Fundamental Medical 1.7 Sporulation 11 Mycology, Laboratory Diagnostic Methods, 1.8 Dimorphism 11 and Antifungal Therapy 1.8.1 Dimorphismand Pathogenesis 12 1.9 Sex in Fungi 13 1. Introduction to Fundamental Medical 1.9.1 Anamorph and Teleomorph Mycology 3 Nomenclature 13 1.10 Classification of Mycoses Based on the 1.1 Topics not Covered, or Receiving Secondary Primary Site of Pathology 13 Emphasis 3 1.10.1 Superficial Mycoses 13 1.2 Biosafety Considerations: Before You Begin 1.10.2 Cutaneous Mycoses 13 Work with Pathogenic Fungi... 3 1.10.3 Systemic OpportunisticMycoses 13 1.2.1 Biological Safety Cabinets (BSC) 4 1.10.4 Subcutaneous Mycoses 13 1.2.2 Precautions to Take in Handling Etiologic 1.10.5 Endemic Mycoses Caused by Dimorphic AgentsthatCauseSystemicMycoses 4 Environmental Molds 13 1.2.3 AdditionalPrecautions at Biosafety 1.11 Taxonomy/Classification: Kingdom Level 3 (BSL 3) 5 Fungi 14 1.2.4 Safety Training 5 1.11.1 The PhylogeneticSpecies Concept for 1.2.5 Disinfectants and Waste Disposal 5 Classification 15 1.3 Fungi Defined: Their Ecologic Niche 5 1.11.2 The Higher Level Classification of 1.4 Medical Mycology 5 Kingdom Fungi 15 1.5 A Brief History of Medical Mycology 6 1.12 General Composition of the Fungal 1.5.1 Ancient Greece 6 Cell 21 1.5.2 MiddleAges 6 1.12.1 Yeast Cell Cycle 21 1.5.3 Twentieth Century 6 1.12.2 Hyphal Morphogenesis 21 1.5.4 Endemic Mycoses in the Americas 6 1.12.3 Cell Wall 22 1.5.5 Era of Immunosuppression in the 1.13 Primary Pathogens 25 Treatment of Cancer, Maintenanceof 1.13.1 Susceptibilityto Primary Organ Transplants,and Autoimmune Pathogens 26 Diseases 7 1.5.6 OpportunisticMycoses 7 1.14 Endemic Versus Worldwide Presence 26 1.5.7 HIV/AIDS 7 1.15 Opportunistic Fungal Pathogens 26 1.5.8 Twenty-first Century 8 1.15.1 Susceptibilityto OpportunisticFungal 1.6 Rationale for Fungal Identification 9 Pathogens: Host Factors 26 1.6.1 Developing the Treatment Plan 9 1.16 Determinants of Pathogenicity 27 vii viii Contents General References in Medical Selected References for Laboratory Mycology 27 Diagnostic Methods in Medical Selected References for Introduction to Mycology 69 Fundamental Medical Mycology 28 Websites Cited 70 Websites Cited 29 Commercial Manufacturers and Suppliers of Questions 30 Fungal Media, Stains, and Reagents 71 Packing and Shipping of Infectious Agents 2. Laboratory Diagnostic Methods in Medical and Clinical Specimens 72 Mycology 31 Questions 72 2.1 Who Is Responsible for Identifying 3A. Antifungal Agents and Therapy 75 Pathogenic Fungi? 31 2.1.1 Role of the Clinical Laboratorian 31 3A.1 Introduction 75 2.1.2 Role of the Physician 31 3A.1.1 Major AntifungalAgents Approved for 2.2 What Methods are Used to Identify Clinical Use 76 Pathogenic Fungi? 31 3A.1.2 Comparison of Antibacterial and 2.2.1 Cultureand Identification 31 Antifungal Agents According to Their 2.3 Laboratory Detection, Recovery, and Intracellular Targets 79 Identification of Fungi in the Clinical 3A.2 Amphotericin B (AmB-deoxycholate) ® (Fungizone , Apothecon Subsidiary of Microbiology Laboratory 33 2.3.1 The Laboratory Manual 33 Bristol-Myers-Squibb) 80 2.3.2 Specimen Collection 33 3A.2.1 Structure 80 2.3.3 Direct Examination 34 3A.2.2 Mode of Action 80 2.3.4 Histopathology 36 3A.2.3 Indications 82 2.3.5 Culture 37 3A.2.4 Formulation 82 2.3.6 Storage and Cryopreservation of Cultures 3A.2.5 Spectrum of Activity 82 for QA and QC in the Clinical Mycology 3A.2.6 Clinical Uses 82 Laboratory 41 3A.2.7 Lipid Formulations of AmB 83 2.3.7 Mediaand Tests for Yeast 3A.2.8 Pharmacokinetics 84 Identification 42 3A.2.9 Interactions 85 2.3.8 MethodsUseful for Mold 3A.2.10 Adverse Reactions 85 ® Identification 45 3A.3 Fluconazole (FLC) (Diflucan , 2.3.9 MicroscopyBasics 53 Pfizer) 86 2.3.10 Use of Reference Laboratories 59 3A.3.1 Structure and Mode of Action 86 2.3.11 Fungal Serology and Biochemical 3A.3.2 Indications 86 Markers of Infection 59 3A.3.3 Fluconazole Pharmacokinetics 87 2.4 Genetic Identification of Fungi 64 3A.3.4 Efficacy 88 2.4.1 Commercial Test 64 3A.3.5 Formulations 88 2.4.2 PeptideNucleic Acid–Fluorescent In Situ 3A.3.6 Interactions 88 Hybridization(PNA-FISH) 64 3A.3.7 Adverse Reactions 88 ® 2.4.3 PCR-Sequencing Method 64 3A.4 Itraconazole (ITC) (Sporanox , Janssen 2.4.4 Nuclear rDNA Complex 64 Pharmaceutica Division of Johnson & 2.4.5 GeneticTools for Species Johnson) 89 Identification 66 3A.4.1 Action Spectrum 89 2.4.6 How Is the Genetic Identification of an 3A.4.2 ITC: Uncertain Bioavailability 89 UnknownFungus Accomplished? 66 3A.4.3 Properties 89 2.4.7 Growth of the Fungus in Pure Culture, 3A.4.4 Pharmacokinetics 89 Extraction and Purification of DNA 66 3A.4.5 Interactions 90 2.4.8 PCR of the Target Sequence 67 3A.4.6 Adverse Reactions 90 ® 2.4.9 PCR Cycle Sequencing 68 3A.5 Voriconazole (VRC) (Vfend , 2.4.10 Assemble the DNA Sequence 68 Pfizer) 90 2.4.11 Perform a BLAST Search 68 3A.5.1 Action Spectrum 90 ® 2.4.12 The MicroSeq System 68 3A.5.2 Pharmacokinetics 90 2.4.13 Other Sequence Databases 68 3A.5.3 Drug Interactions 91 General References for Laboratory 3A.5.4 Adverse Reactions 91 ® Diagnostic Methods in Medical 3A.6 Posaconazole (PSC) (Noxafil , Mycology 69 Schering-Plough/Merck & Co.) 91 Contents ix 3A.6.1 Action Spectrum 91 3A.14.1 Modeof Action 99 3A.6.2 Pharmacokinetics 91 3A.14.2 Action Spectrum 99 3A.6.3 Drug Interactions 92 3A.14.3 Indications 99 3A.6.4 Adverse Reactions 92 3A.14.4 DosageRegimen 99 3A.7 Azole Resistance Mechanisms 92 3A.14.5 Metabolism 99 3A.7.1 Alteration of Target Enzyme 3A.14.6 Adverse Reactions 100 (Lanosterol Demethylase) 92 3A.15 Combination Therapy 100 3A.7.2 Overexpression of Target 3A.16 Suppressive or Maintenance Enzyme 92 Therapy 100 3A.7.3 Increased Efflux of Drug, CDR Efflux 3A.17 Prophylactic Therapy 100 Pumps 92 3A.17.1 Bimodal Period of Risk 101 3A.7.4 Bypass Pathways 92 3A.17.2 Fluconazole and Alternativesfor 3A.7.5 Loss of Heterozygosityin Primary Prophylaxis 101 Chromosome 5 and Azole 3A.17.3 Prophylaxis in Patients During the Resistance 92 Pre-engraftment Period with a History 3A.7.6 Azole Resistance in Aspergillus of InvasiveMold Infections 102 Species 93 3A.17.4 Prophylaxis in the Post-engraftment 3A.8 Echinocandins 93 Period 102 3A.8.1 Mode of Action 93 3A.18 Empiric Therapy 102 3A.8.2 Spectrum of Activity 93 ® 3A.19 Innately Resistant Fungi 103 3A.9 Caspofungin (CASF) (Cancidas , 3A.19.1 Innately Resistant Molds 103 Merck) 94 3A.19.2 Innately Resistant Yeasts 103 3A.9.1 Action Spectrum 94 General Reference for Antifungal Agents 3A.9.2 Dosage 95 and Therapy 103 3A.9.3 Pharmacokinetics 95 Selected References for Antifungal Agents 3A.9.4 Drug Interactions 95 and Therapy 103 3A.9.5 Adverse Reactions 95 3A.10 Micafungin (MCF) (Mycaminet®, Astellas Websites Cited 105 Pharma, Inc.) 95 Questions 105 3A.10.1 Indications 95 3A.10.2 Dosage 95 3B. Antifungal Susceptibility Tests 107 3A.10.3 Metabolism 96 3B.1 Antifungal Susceptibility Tests 3A.10.4 Drug Interactions 96 3A.11 Anidulafungin (ANF) (Eraxis®, Defined 107 3B.2 National and International Standards for Pfizer) 96 AFS Tests 107 3A.11.1 Indications 96 3B.3 Objective of AFS Tests 107 3A.11.2 Invasive Candidiasis 96 3B.4 Minimum Inhibitory Concentration (MIC) 3A.11.3 Molds 96 3A.11.4 Dosage 96 of an Antifungal Drug Defined 107 3A.11.5 Metabolism 96 3B.4.1 MIC50 and MIC90 108 3B.5 Broth Microdilution (BMD) 3A.11.6 Drug Interactions 97 3A.11.7 Adverse Reactions 97 Method 108 3A.12 Terbinafine (TRB) (Lamisil®, 3B.6 Clinical Indications for AFS Novartis) 97 Testing 108 3A.12.1 Mode of Action 97 3B.7 Correlation Between the In Vitro 3A.12.2 Action Spectrum 97 Determined MIC and the Clinical Efficacy 3A.12.3 Drug Synergy 97 of Drug Therapy 108 3A.12.4 Metabolism 97 3B.7.1 How Are the Conditionsof 3A.12.5 Adverse Reactions 98 “Susceptible” or “Resistant” 3A.13 5-Fluorocytosine (Flucytosine, 5FC) Determined? 109 ® (Ancobon , Valeant 3B.7.2 What Are Breakpoints? 109 Pharmaceuticals) 98 3B.7.3 Minimum Effective 3A.13.1 Indications 98 Concentration 109 3A.13.2 Combination Therapy 98 3B.8 AFS Methods Currently Available for Use 3A.13.3 Metabolism 98 in the Clinical Laboratory 110 3A.13.4 Adverse Reactions 98 3B.8.1 Broth Microdilution(BMD) 3A.14 Griseofulvin (Grifulvin V, Ortho Method 110 Pharmaceutical Corp.) 99 3B.8.2 Etest® 110 x Contents 3B.8.3 Disk Diffusion Method 110 Selected References for 3B.9 Which Laboratories Conduct AFS Blastomycosis 137 Tests? 110 Questions 138 3B.10 Principles of AFS Tests 110 3B.10.1 Standard Method for AFS Testing of 5. Coccidioidomycosis 141 Yeasts 110 3B.10.2 Modifications Suggested to Improve 5.1 Coccidioidomycosis-at-a-Glance 141 Performance of the BMD Method for 5.2 Introduction/Disease Definition 141 Yeast 112 5.3 Case Presentations 142 3B.10.3 Commercial BMD Method with 5.4 Diagnosis 143 Precoated Drug Panels: A 5.5 Etiologic Agents 143 CLSI-Approved Method for AFS 5.6 Geographic Distribution/Ecologic Testing of Yeasts and Molds 113 Niche 144 3B.10.4 Standardization of AFS Tests for 5.7 Epidemiology 147 Molds, M38-A2:Broth Microdilution 5.7.1 Incidence and Prevalence 147 for Molds 114 ® 5.7.2 Effect of Weather on Annual Fluctuations 3B.10.5 Etest (bioMe´rieux, Marcy l’Etoile, in Prevalence of France) 114 Coccidioidomycosis 148 3B.10.6 Disk Diffusion AFS Tests 117 3B.10.7 VITEK 2® System for AFS 5.8 Risk Groups/Factors 149 (bioMe´rieux, Marcy l’Etoile, 5.9 Transmission 150 France) 118 5.10 Determinants of Pathogenicity and 3B.10.8 Flow Cytometry AFS Test 118 Pathogenesis 151 3B.11 Summary of the Current Status of 5.10.1 Allergic Findings 151 Antifungal Susceptibility Testing 119 5.10.2 Pathology 151 Selected References for Antifungal 5.10.3 Host Factors 151 Susceptibility Testing 120 5.10.4 Pathogenesis 153 5.10.5 Vaccine Development 154 Questions 121 5.10.6 Attenuated LiveChitinase Mutant C.posadasii 154 5.11 Clinical Forms 155 Part Two Systemic Mycoses Caused by Dimorphic 5.12 Veterinary Forms 156 Environmental Molds (Endemic Mycoses) 5.13 Therapy 156 5.14 Laboratory Detection, Recovery, and 4. Blastomycosis 125 Identification 158 Selected References for 4.1 Blastomycosis-at-a-Glance 125 Coccidioidomycosis 162 4.2 Introduction/Disease Definition 125 Websites Cited 163 4.3 Case Presentations 126 Questions 164 4.4 Diagnosis 127 4.5 Etiologic Agent 127 6. Histoplasmosis 165 4.6 Geographic Distribution/Ecologic Niche 128 6.1 Histoplasmosis-at-a-Glance 165 4.7 Epidemiology 129 6.2 Introduction/Disease Definition 165 4.8 Risk Groups/Factors 129 6.3 Case Presentations 166 4.9 Transmission 129 6.4 Etiologic Agents 169 4.10 Determinants of Pathogenicity 130 6.5 Geographic Distribution/Ecologic 4.10.1 Pathogenesis 130 Niche 170 4.10.2 Host Factors 130 6.6 Epidemiology 171 4.10.3 Microbial Factors 130 6.6.1 Incidence and Prevalence 171 4.11 Clinical Forms 131 6.6.2 Risk Groups/Factors 171 4.12 Veterinary Forms 133 6.7 Transmission 171 4.13 Therapy 133 6.8 Determinants of Pathogenicity 172 4.14 Laboratory Detection, Recovery, and 6.8.1 Host Factors 172 Identification 134 6.8.2 Microbial Factors 173 General Reference for Blastomycosis 137 6.9 Clinical Forms 175 Contents xi 6.10 Veterinary Forms 178 8.14 Laboratory Detection, Recovery, and 6.11 Therapy 179 Identification 208 6.12 Laboratory Detection, Recovery, and Selected References for Penicilliosis 212 Identification 180 Website Cited 212 Selected References for Questions 212 Histoplasmosis 184 Websites Cited 185 9. Sporotrichosis 215 Questions 185 9.1 Sporotrichosis-at-a-Glance 215 9.2 Introduction/Disease Definition 215 7. Paracoccidioidomycosis 187 9.3 Case Presentations 216 7.1 Paracoccidioidomycosis-at- 9.4 Diagnosis 218 a-Glance 187 9.5 Etiologic Agents 218 7.2 Introduction/Disease Definition 187 9.6 Geographic Distribution/Ecologic 7.3 Case Presentation 188 Niche 219 7.3.1 Oral Lesions in a Legionnaire (Horre´ 9.7 Epidemiology 219 et al., 2002) 188 9.7.1 Risk Groups/Factors 220 7.4 Etiologic Agent 188 9.8 Transmission 220 7.5 Geographic Distribution/Ecologic 9.9 Determinants of Pathogenicity 220 Niche 189 9.9.1 Host Factors 220 7.6 Epidemiology 189 9.9.2 Microbial Factors 221 7.6.1 Incidence 189 9.10 Clinical Forms 223 7.6.2 Risk Groups/Factors 189 9.11 Human–Animal Interface 224 7.7 Transmission 191 9.12 Therapy 225 7.8 Determinants of Pathogenicity 191 9.13 Laboratory Detection, Recovery, and 7.8.1 Host Factors 191 Identification 227 7.8.2 Microbial Factors 191 Selected References for 7.9 Clinical Forms 192 Sporotrichosis 230 7.10 Veterinary Forms 193 Website Cited 231 7.11 Therapy 194 Questions 231 7.12 Laboratory Detection, Recovery, and Identification 195 10A. Less Frequent Mycoses Caused by Selected References for Dimorphic Environmental Molds: Paracoccidioidomycosis 198 Adiaspiromycosis 233 Questions 199 10A.1 Adiaspiromycosis-at- 8. Penicilliosis 201 a-Glance 233 10A.2 Introduction/Disease Definition 234 8.1 Penicilliosis-at-a-Glance 201 10A.3 Case Summaries 234 8.2 Introduction/Disease Definition 201 10A.4 Diagnosis 235 8.3 Case Presentation 202 10A.5 Etiologic Agents 235 8.4 Diagnosis 203 10A.6 Geographic Distribution/Ecologic 8.5 Etiologic Agents 203 Niche 235 8.6 Geographic Distribution/Ecologic 10A.7 Epidemiology/Risk Niche 203 Groups/Factors 235 8.7 Epidemiology 204 10A.8 Transmission 235 8.7.1 Incidence 204 10A.9 Determinants of Pathogenicity 236 8.7.2 Molecular Epidemiology 205 8.8 Risk Groups/Factors 205 10A.10 Clinical Forms 236 8.9 Transmission 205 10A.11 Veterinary Forms 236 8.10 Determinants of Pathogenicity 205 10A.12 Therapy 236 8.10.1 Host Factors 205 10A.13 Laboratory Detection, Recovery, and 8.10.2 MicrobialFactors 205 Identification 236 8.11 Clinical Forms 206 Selected References for 8.12 Veterinary Forms 208 Adiaspiromycosis 238 8.13 Therapy 208 Questions 238 xii Contents 10B. Less Frequent Mycoses Caused by 11.10.2 Microbial Factors 276 Dimorphic Environmental Molds 11.11 Therapy 282 (Endemic Mycoses): Lobomycosis 11.12 Laboratory Detection, Recovery, and (Jorge Loˆbo’s Disease) 241 Identification 286 11.13 Less Common Opportunistic Yeast 10B.1 Lobomycosis-at-a-Glance 241 Genera 292 10B.2 Introduction/Disease Definition 242 11.13.1 Geotrichumcapitatum 10B.3 Case Presentations 242 (Blastoschizomycescapitatus) 292 10B.4 Diagnosis 244 11.13.2 RhodotorulaSpecies 294 10B.5 Etiologic Agent 244 11.13.3 Saccharomycescerevisiae 295 10B.6 Geographic Distribution/Ecologic Selected References for Candidiasis 297 Niche 244 Questions 301 10B.7 Epidemiology 244 10B.8 Risk Groups/Factors 244 12. Cryptococcosis 303 10B.9 Transmission 244 10B.10 Determinants of Pathogenicity 245 12.1 Cryptococcosis-at-a-Glance 303 10B.10.1 Host Factors 245 12.2 Introduction/Disease 10B.10.2 Microbial Factors 245 Definition 303 10B.11 Clinical Forms 245 12.3 Case Presentations 304 10B.12 Veterinary Forms 245 12.4 Etiologic Agents 307 10B.13 Therapy 246 12.5 Geographic Distribution/Ecologic 10B.14 Laboratory Detection, Recovery, and Niche 311 Identification 246 12.6 Epidemiology 312 Selected References for 12.7 Risk Groups/Factors 315 Lobomycosis 246 12.8 Transmission 316 Questions 247 12.9 Determinants of Pathogenicity 316 12.9.1 Host Factors 316 12.9.2 Microbial Factors 318 Part Three Systemic Mycoses Caused by 12.10 Clinical Forms 321 Opportunistic Yeasts and Pneumocystis 12.11 Veterinary Forms 323 12.12 Therapy 324 11. Candidiasis and Less Common Yeast 12.13 Laboratory Detection, Recovery, and Genera 251 Identification 326 General References for 11.1 Candidiasis-at-a-Glance 251 Cryptococcosis 329 11.2 Introduction/Disease Definition 251 Selected References for 11.3 Case Presentations 252 Cryptococcosis 329 11.4 Diagnosis 255 Websites of Interest 11.5 Etiologic Agents and their Ecologic or Cited 331 Niches 255 Questions 331 11.5.1 Classification of Candida Species 255 11.5.2 Less Common Candida Species of 13. Pneumocystosis 333 Clinical Importance 257 13.1 Pneumocystosis-at-a-Glance 333 11.6 Epidemiology 258 13.2 Introduction/Disease 11.6.1 Major Types of Candidiasis 258 Definition 333 11.7 Risk Groups/Factors 264 13.3 Case Presentation 334 11.7.1 Invasive Candidiasis 264 13.4 Etiologic Agent 335 11.7.2 Mucosal Candidiasis 264 13.5 Geographic Distribution/Ecologic 11.7.3 Cutaneous Candidiasis 265 11.8 Transmission 265 Niche 336 11.9 Clinical Forms 266 13.6 Epidemiology 337 11.10 Determinants of Pathogenicity 273 13.7 Risk Groups/Factors 339 11.10.1 Host Factors 273 13.8 Transmission 340