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دانلود کتاب (Eğitim Tanrısı) John E. Bennett, Raphael Dolin, Martin J. Blaser - Mandell, Douglas, and Bennett’s Principles and Practice of Infectious Diseases-Elsevier (2019)
دانلود کتاب (Eğitim Tanrısı) John E. Bennett, Raphael Dolin, Martin J. Blaser - Mandell, Douglas, and Bennett’s Principles and Practice of Infectious Diseases-Elsevier (2019)
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(Eğitim Tanrısı) John E. Bennett, Raphael Dolin, Martin J. Blaser - Mandell, Douglas, and Bennett’s Principles and Practice of Infectious Diseases-Elsevier (2019)
ویرایش: نویسندگان: (Eğitim Tanrısı) John E. Bennett, Raphael Dolin, Martin J. Blaser - Mandell, Douglas, and Bennett’s Principles and Practice of Infectious Diseases-Elsevier (2019) copy سری: ISBN (شابک) : 9780323482554, 2019944671 ناشر: سال نشر: 2020 تعداد صفحات: [5407] زبان: English فرمت فایل : PDF (درصورت درخواست کاربر به PDF، EPUB یا AZW3 تبدیل می شود) حجم فایل: 98 Mb
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COVER Mandell, Douglas, and Bennett's Principles and Practice of Infectious Diseases Copyright Page Contributors Preface to the 9th Edition COPYRIGHT Contributors Preface to the 9th Edition I Basic Principles in the Diagnosis and Management of Infectious Diseases A Microbial Pathogenesis 1 A Molecular Perspective of Microbial Pathogenicity Attributes of Microbial Pathogens Evolution of Bacterial Pathogenicity Regulation of Bacterial Pathogenicity Close Encounters: Pathogens as Cell Biologists Identification and Characterization of Virulence Genes Molecular Microbiology at the Bedside: Pathogen Detection, Pathogen Discovery, and Genomic Profiling Dedication Key References References 2 The Human Microbiome of Local Body Sites and Their Unique Biology Defining the Human Microbiome The Human Microbiome as a Complex Ecosystem Composed of Multiple Body Site Habitats and Niches From Whence and When Do Our Microbiomes Come? Oral Microbiome Associations Between Oral Microbiota and Disease States Skin and Nasopharynx Airway and Pulmonary Microbiome Gastrointestinal Tract Esophagus Stomach Intestine (Small and Large) Vaginal Microbiome Bacterial Vaginosis: An Example of a Prevalent Pathobiont in the Vaginal Microbiome Group B Streptococcus The Human Microbiome During Pregnancy Summary and Future Directions Key References References 3 Prebiotics, Probiotics, and Synbiotics Short View Summary Issues Regarding the Complexity and Variability of Probiotics Clinical Studies of Probiotics Proposed Mechanisms of Action of Probiotics Potential Adverse Effects of Probiotic Therapy Fecal Microbiota Transplant for Infectious Conditions Other Than Clostridioides Difficile Infection Summary and Future Directions Key References References B Host Defense Mechanisms 4 Innate (General or Nonspecific) Host Defense Mechanisms Physical and Chemical Barriers to the Entry of Microorganisms Into the Body Skin Mucous Membranes Respiratory Tract Gastrointestinal Tract Genitourinary Tract Eye Innate Immune Sensing of Invading Pathogens Phagocytosis Autophagy The Inflammatory Response Cytokines and Chemotaxis Pathogen Interference With Innate Immune Responses Key References References 5 Adaptive Immunity Short View Summary Immunoglobulin Structure Basic Antibody Structure F(ab′)2, Fab, and Fc Pieces Antigen Binding, Affinity, and Avidity Immunoglobulin Classes Immunoglobulin M Immunoglobulin G Immunoglobulin A Immunoglobulin D Immunoglobulin E Effector Functions Mediated by Antibodies Blocking or Neutralization Complement Activation Opsonization Antibody-Dependent Cellular Cytotoxicity Direct Antibody-Mediated Antimicrobial Functions Antibody-Mediated Catalysis Kinetics of Antibody Production and Diagnosis of Infections Laboratory Measurement of Antibodies Quantification of Total Immunoglobulin Serum Protein Electrophoresis for Monoclonal Gammopathies Measurement of Functional Antibody Western Blot Agglutination and Complement Fixation Immunofluorescence and Immunohistochemistry Enumeration of Antibody-Producing B Cells: The ELISPOT Assay Assays to Measure Antigen Measurement of Immune Complexes B-Cell Maturation and Immunoglobulin Production DNA Rearrangement and Generation of Diverse Antigen-Binding Sites Deletion of Autoreactive Clones Antigen Stimulation: First Signal Coreceptors Amplify or Suppress Antigen Signaling Second Signals and Interactions Between B Cells and T Cells How B Cells Find and Activate T Cells T-Cell–Independent Antigens Downregulation of Antibody Production B1 Cells Antibody-Mediated Pathology Gell and Coombs Classification of Hypersensitivity Responses Type I Hypersensitivity Type II Hypersensitivity Origin of Autoreactive Antibodies Type III Hypersensitivity Hypergammaglobulinemia Immunodeficiencies Immunoglobulin A Deficiency Agammaglobulinemias Hyper–Immunoglobulin M Syndrome Common Variable Immunodeficiency Immunoglobulin G Subclass Deficiencies Selective Immunodeficiencies Combined T-Cell and B-Cell Defects Malignancies Therapeutic Uses of Antibodies Passive Immunization Intravenous Immune Globulin Replacement Monoclonal Antibodies Key References References 6 Cell-Mediated Defense Against Infection Short View Summary T-Cell Subsets and Phenotypic Diversity CD4 T Cells Th1 T Cells Th2 T Cells Th17 T Cells T-Regulatory Cells Helper T-Follicular Cells Plasticity of Helper T-Cell Subsets CD8 T Cells NKT Cells and T Cells With a Restricted αβ TCR Repertoire γδ T Cells T-Cell Memory T-Cell Development and Lymphoid Tissue Organization Thymic Selection of CD4 and CD8 T Cells Lymphoid Anatomy Lymph Nodes Spleen Mucosa-Associated Lymphoid Tissue T-Cell Activation Organization of the Major Histocompatibility Complex Antigen Presentation to T Lymphocytes via MHC Class I MHC Class I Structure MHC Class I Antigen-Processing Pathway Viral Interactions With the MHC Class I Antigen-Processing Pathway MHC Class I Cross-Presentation Antigen Presentation to T Lymphocytes via MHC Class II MHC Class II Structure MHC Class II Antigen-Processing Pathway CD1 and Antigen Presentation Innate Immune Recognition: Setting the Stage for T-Cell Responses Molecular Recognition of Microbial Products Toll-Like Receptors NOD-Like Receptors, RIG-I–Like Receptors, the Cyclic GMP-AMP Synthase–Stimulator of Interferon Genes Sensing Pathway, and the Inflammasome C-Type Lectin Receptors Links Between Innate Immune Recognition and Adaptive Immune Responses Dendritic Cells Microbial Pathogenesis and the Cellular Immune System Viral Infections Infections With Intracellular Bacteria and Fungi Phagosomal Pathogens Cytoplasmic Pathogens Infections With Extracellular Bacteria and Fungi Primer on Basic Immunologic Techniques Characterizing and Measuring Pathogen-Specific Immunity Key References References 7 Mucosal Immunity Short View Summary Specialization of Host Responses in Mucosal Tissues The Challenge Adaptation of Mucosal Immune Responses Microbial Communities and Development of Mucosal Immune Responses Induction of Mucosal Immune Responses Epithelial Cell Responses and Immunophysiology Antigen-Presenting Cells Innate Lymphoid Cells Sensing Mucosal Microbiota Sensing Metabolites Discrimination Between a Commensal and a Pathogen Adaptive Immunity to Mucosal Stimulation Immunologic Homeostasis in Mucosal Tissues When Mucosal Responses Go Wrong Mucosal Host Response Defines Pathogenicity Good Bugs, Bad Bugs, and the Hygiene Hypothesis Mucosal Immunization Role of Mucosal Immunity: Beyond the Mucosa Conclusions Key References References 8 Granulocytic Phagocytes Neutrophils Development Emergency Granulopoiesis Mitotic and Postmitotic Cells Morphologic and Structural Characteristics Azurophilic Granules Peroxidase-Negative Granules Nucleus and Actin Cytoskeleton Organelles in the Cytoplasm Surface Receptors Homeostasis of the Circulating Neutrophil Population Distribution of Neutrophils Inflammatory Response Priming Step 1: Neutrophil Recruitment Selectin-Mediated Adhesion and Rolling β2-Integrin–Mediated Cell-Cell Interaction Tissue Migration Production of Inflammatory Mediators Role of Chemokines in Neutrophil Recruitment Step 2: Phagocytosis Opsonins Phagocytic Receptors Ingestion Step 3: Fate of the Ingested Microbe Respiratory Burst Reactive Oxygen Species NADPH Oxidase (Respiratory Burst Oxidase) Translocation of Cytosolic Components p40phox Rac2 Nonphagocyte Oxidases: The NOX Protein Family Degranulation Step 4: Resolution of the Inflammatory Response Apoptosis Proinflammatory Molecules Alter Apoptosis Microbial Pathogens Influence Neutrophil Fate Neutrophils as “Trojan Horses” Bioactive Lipid Mediators Microbicidal Mechanisms Intraphagosomal Killing of Microbes Oxygen-Dependent Killing of Microbes Oxygen-Independent Killing of Microbes Extracellular Microbicidal Activity Neutrophils and Microbial Evasion of Host Defense Microbial Responses to Neutrophils Microbial Targeting of Neutrophil Surface Molecules Survival of Microbes After Ingestion by Neutrophils Eosinophils Development and Characteristics Eosinophil Surface Receptors Eosinophil Granules Recruitment From Circulation Role in Host Defense Moderation of Type I Hypersensitivity Reactions Eosinophil-Mediated Tissue Injury Key References References 9 Complement and Deficiencies Short View Summary Complement Synthesis, Catabolism, and Distribution Complement Activation Overview: C3, the Linchpin of the Complement System Generation of the Classical-Pathway C3 Convertase Generation of the Alternative-Pathway C3 Convertase The “Tickover” Model The Properdin-Directed Model Assembly of the Membrane Attack Complex Regulation of Complement Activation Regulation of C1 Activation Regulation of the C3 Convertases Regulation of the Membrane Attack Complex Basis for Discriminating Between Host and Microbial Cell Surfaces Complement Receptors Families of Complement Proteins Complement-Mediated Functions Elimination of Pathogens Modulation of Adaptive Immune Responses Clearance of Immune Complexes and Apoptotic Cells Complement and Metabolism Complement and Cancer Complement in Tissue Regeneration and Organogenesis Microbial Interactions With the Complement System Complement Deficiency States Incidence General Aspects of the Molecular Basis for Complement Deficiencies Classical-Pathway Deficiencies Clinical Aspects Immune Disorders Pathophysiologic roles for complement in systemic lupus erythematosus. Infectious Diseases Molecular Aspects Lectin-Pathway Deficiencies Deficiency of Mannose-Binding Protein Clinical Aspects Molecular Aspects Deficiency of Ficolin-3 Deficiencies of Collectin 11 (CL-K1) and MASP-1 Clinical Aspects Molecular Aspects Deficiency of Mannose-Binding Protein–Associated Serine Protease 2 (MASP-2) Alternative-Pathway Deficiencies Clinical Aspects Molecular Aspects C3 Deficiency Clinical Aspects Molecular Aspects Late Complement Component Deficiencies Clinical Aspects Meningococcal Disease in Complement Deficiency Molecular Aspects Deficiencies of Complement Regulatory Proteins Hereditary Angioedema: C1 Inhibitor Deficiency Factor H Deficiency Clinical Aspects: Membranoproliferative Glomerulonephritis Type II Clinical Aspects: Atypical Hemolytic-Uremic Syndrome Clinical Aspects: Age-Related Macular Degeneration CD59 Deficiency: Paroxysmal Nocturnal Hemoglobinuria Complement in Disease States Infectious Diseases Rheumatologic Disorders Renal Disorders Evaluation and Treatment of Complement Disorders Evaluation Treatment Acknowledgment Key References References 10 Human Genetics and Infection Short View Summary Magnitude of the Host Genetic Effect Approaches Diseases Malaria Mycobacterial Diseases Viral Diseases Human Immunodeficiency Virus Infection and Acquired Immunodeficiency Syndrome Persistent Hepatitis Other Viral Diseases Other Infectious Disease Phenotypes Specific Susceptibility and Resistance Genes Blood Groups Human Leukocyte Antigens Mannose-Binding Lectin Toll-Like Receptor Pathway Genes Evolutionary Perspective Applications Key References References 11 Nutrition, Immunity, and Infection Epidemiology of Malnutrition Malnutrition and Immune Function Specific Nutrients and Their Roles in Immunity Fat-Soluble Vitamins Vitamin A Vitamin D Vitamin E Water-Soluble Vitamins Vitamin C Vitamin B6 Folate Vitamin B12 Trace Metals Zinc Selenium Iron Fatty Acids Overnutrition: Obesity and Infectious Diseases Special Populations: Clinical Trials of Nutritional Supplementation to Reduce Infection Risk Surgical and Critically Ill Patients Total Parenteral Nutrition Versus Enteral Nutrition Immunonutrition Human Immunodeficiency Virus/Acquired Immunodeficiency Syndrome Strategies to Combat Weight Loss and Wasting Associated With Human Immunodeficiency Virus Macronutrient Supplementation Micronutrient Supplementation Older Adults Nutritional Supplements in Older Adults: Effects on Immunity and Clinical Outcomes Multivitamin and Trace Mineral Supplements Vitamin E Zinc Host Nutritional Status and Pathogen Virulence Acknowledgments Key References References 12 Evaluation of the Patient With Suspected Immunodeficiency Short View Summary Index of Suspicion Initial Evaluation Lymphocyte Immune Defects T Cells and Cell-Mediated Immunity B Cells and Humoral Immunity Phagocyte Immune Defects: Neutrophils Neutropenia Chédiak-Higashi Syndrome Leukocyte Adhesion Deficiency Neutrophil-Specific Granule Deficiency Myeloperoxidase Deficiency Chronic Granulomatous Disease Defects Affecting Phagocyte Signaling Phagocyte and Lymphocyte Defects Affecting Mononuclear Cells Hyperimmunoglobulin E–Recurrent Infection Syndrome (Job Syndrome) GATA2 Deficiency Complement-Mediated Immunity Acquired Immunodeficiencies Key References References C Epidemiology of Infectious Disease 13 Applied Epidemiology for the Infectious Diseases Physician What Is Epidemiology? What Can Epidemiology Tell the Infectious Disease Clinician? The Epidemiologic Triad Model: Agent, Host, and Environment The Sufficient-Component Cause Model of Epidemiology Other Methods to Characterize Infection Transmission Descriptive Epidemiology Analytic Epidemiology Experimental Studies Observational Studies Cohort Studies Case-Control Studies Cross-Sectional and Ecologic Studies Determining the Appropriate Epidemiologic Study Design Basic Biostatistics Measures of Disease Frequency Ratios, Proportions, and Rates Incidence Prevalence Measures of Association Two-by-Two Tables Prevalence Ratio and Prevalence Odds Ratio Statistical Significance P Values Confidence Intervals Disease Surveillance Classification of Surveillance Disease Prevention Disease Control: Quarantine and Isolation Outbreak Investigation Primer Outbreak Epidemiology General Key Outbreak Principles Incubation Period Epidemic Curves Transmission Modes Chains of Transmission Types of Outbreaks Foodborne Outbreaks Nosocomial Outbreaks Respiratory and Other Person-to-Person Outbreaks Sexually Transmitted Outbreaks Zoonotic and Vector-Borne Outbreaks Outbreak Investigation and Response Consequences of an Outbreak Key References References 14 Emerging and Reemerging Infectious Disease Threats Short View Summary Infectious Causes of Chronic Diseases Factors That Favor Disease Spread Antimicrobial Resistance Acute Respiratory Tract Infections Human Metapneumovirus Human Coronaviruses Human Bocaviruses Emerging Influenza Viruses Reservoirs of Influenza A Influenza A and Pandemics Novel Influenza A Viruses Influenza A(H5N1) Influenza A(H5N6) Influenza A(H7N9) Other Influenza A Virus Subtypes Variant Influenza A Infections From Swine Influenza Risk Assessment Enteric Diseases Routes of Transmission for Enteric Pathogens International Spread: Cholera in the Western Hemisphere Evolution of Enteric Pathogens Noroviruses Future Trends Vector-Borne Diseases The Aedes-Transmitted Viruses: Dengue, Zika, Yellow Fever, and Chikungunya Dengue Zika Yellow Fever Chikungunya Plasmodium vivax, Plasmodium knowlesi, and Zoonotic Malaria Tick-borne Pathogens Ebola and Marburg Hemorrhagic Fevers Conclusion: Controlling the Threats Acknowledgments Key References References 15 Bioterrorism Defining Biological Warfare, Bioterrorism, and Biocrimes History of Biological Weapons Development and Use in Warfare and Against Insurgencies Pre–World War I Biological Weapons Development and Use Development and Use of Biological Weapons During World War I Development and Use of Biological Weapons During World War II Biological Weapons in the Post–World War II Period Through the End of the Cold War Offensive Biological Weapons Programs in the United States Limiting Use of Biological Weapons: the Biological Weapons Convention Monitoring and Compliance Under the Biological Weapons Convention Civilian Research in the Soviet Union Military Activities in the Soviet Union Iraq’s Biological Weapons Program History of Biological Weapons Use to Commit Acts of Bioterrorism 20th-Century Bioterrorism Against Humans: The Rajneeshee Cult 21st-Century Bioterrorism Against Humans: The Anthrax Letters Limiting Development and Use of Biological Weapons by Terrorists Classifications of Biological Agents of Concern Formulation of the CDC List of Category A, B, and C Agents/Diseases of Bioterrorism The CDC and NIAID Biodefense and Priority Pathogen Lists in Perspective Dual Use Research of Concern, Gain-of-Function Research, and Synthetic Biology Addressing the Highest Priority Biological Agents Approval and Use of Medical Countermeasures for Priority Biological Agents Emergency Use Authorization The Animal Rule Use for Approval of Drugs, Vaccines, and Biologics Clinical Aspects of High-Consequence Bioterrorism Pathogens Variola (Smallpox) Virus Bacillus anthracis Clostridium botulinum Toxin Yersinia pestis Francisella tularensis Rickettsia prowazekii Burkholderia mallei Burkholderia pseudomallei Viral Hemorrhagic Fever Viruses Bioterrorism Incidents Clinical Provider Preparedness and Response Supplementing Health Care Provider Resources Supplementing MCMs With the Strategic National Stockpile Health Care Facility Preparedness and Response Public Health Preparedness and Response Communication Epidemiology Laboratory Preparedness and Response Surveillance Acknowledgment Key References References D Clinical Microbiology 16 The Clinician and the Microbiology Laboratory: Test Ordering, Specimen Collection, and Result Interpretation Short View Summary Microorganisms Hazardous to Laboratory Workers Taxonomy Infection Prevention and Control Bacterial, Mycobacterial, and Fungal Identification Matrix-Assisted Laser Desorption Ionization Time-of-Flight Mass Spectrometry Antibacterial Susceptibility Testing Antimicrobial Stewardship Specimen Selection, Collection, Transportation, and Initial Processing Specific Specimen Guidelines and Initial Laboratory Processing Blood Cultures Intravenous Catheter Tips Cerebrospinal Fluid Peritoneal, Pleural, and Pericardial Fluids Bone and Joint Specimens Skin and Soft Tissue Specimens Respiratory Tract Specimens Urine Stool Vaginitis and Vaginosis Diagnostics Genital Lesions and Syphilis Diagnostics Urethritis and Cervicitis Diagnostics Helicobacter pylori Diagnostics Mycobacterium tuberculosis Diagnostics Acknowledgments Key References References E Antiinfective Therapy 17 Principles of Antiinfective Therapy Short View Summary The Antibiotic Miracle: What We Are Fighting for A Brief History of “Antibiotics” The Power of Antibiotics: What We Stand to Lose Due to Resistance The Societal Trust of Antibiotics Must Underpin Principles of Use Antibiotics Are a Societal Trust Fundamental Principles of Antibiotic Therapy 1. Proper Selection of Empirical Antibiotics Starts With an Accurate Differential Diagnosis That Includes Likely Bacterial Infection 2. Even in a Patient With a Bacterial Infection, Treat Only When Therapy Will Alter the Patient’s Clinical Course 3. Empirically Target Microbes That Cause the Diseases in the Differential Diagnosis 4. A Lower Threshold for Empirical Therapy Should Be Used in Critically Ill Patients 5. Host Factors Affect Breadth of Empirical Therapy by Altering Likely Microbial Causes of Infection 6. Pharmacokinetic-Pharmacodynamic Principles Can Influence Optimal Treatment 7. Deescalate Antibiotic Therapy Based on Microbiology Results and Clinical and Biomarker Responses 8. If Therapy Is Not Working, Consider Source Control and Alternative Diagnoses Before Blaming Resistance and Broadening Therapy 9. Distinguish New Infection From Failure of Initial Therapy 10. The Duration of Therapy Should Be Evidence Based and Short Course Whenever Possible Controversial Principles of Antibiotic Therapy The Greatly Misunderstood Dogma of Bactericidal Versus Bacteriostatic Combination Therapy: The Good, the Bad, and the Ugly The Good The Good #1: Ensuring Adequate Empirical Coverage The Good #2: Preventing Resistance Emergence The Good #3: Improving Cure Slow-growing infections/nonreplicating persisters. Exotoxin-mediated necrotizing infections. Eukaryotic infections. “The Bad”: Redundant Definitive Therapy for Typical Bacterial Infections “The Ugly”: Imperfect Data and Controversy Controversy Over Superior Outcomes With Combination Therapy for Some Infections Controversy Over Preventing Emergence of Resistance Conclusions Key References References 18 Molecular Mechanisms of Antibiotic Resistance in Bacteria Molecular Genetics of Antibiotic Resistance Plasmids Transposable Genetic Elements DNA Integration Elements Molecular Mechanisms of Antibiotic Resistance Enzymatic Inhibition of Antimicrobial Activity β-Lactamases Extended-Spectrum β-Lactamases TEM-derived β-lactamases. SHV-derived β-lactamases. CTX-M–derived extended spectrum β-lactamases. OXA-derived β-lactamases. AmpC β-lactamase enzymes. Carbapenemases. Gram-Positive Bacterial β-Lactamases Anaerobic Bacteria Contribution of β-Lactamases to β-Lactam Antibiotic Resistance Aminoglycoside Resistance–Modifying Enzymes Chloramphenicol Acetyltransferase Macrolide-, Lincosamide-, Streptogramin-Inactivating Enzymes Tetracycline Inactivation Decreased Permeability of Bacterial Membranes Outer Membrane Permeability Inner Membrane Permeability Promotion of Antibiotic Efflux Tetracyclines Macrolides and Streptogramins β-Lactams Fluoroquinolones Altered Target Sites Alteration of Ribosomal Target Sites Macrolides, Lincosamides, Streptogramins Tetracyclines Aminoglycosides Ketolides Oxazolidinones Alteration of Cell Wall Precursor Targets: Glycopeptides Enterococci Staphylococci Alteration of Target Enzymes β-Lactams MRSA Resistance Quinolones Sulfonamides Trimethoprim Protection of Target Site Tetracyclines Fluoroquinolones Overproduction of Target Sulfonamides and Trimethoprim Bypass of Antibiotic Inhibition Resistance to Newer, Older, and Miscellaneous Agents Oxazolidinones Fosfomycin Metronidazole Multidrug-Resistance Mechanisms Among Bacteria Control of Antibiotic Resistance Key References References 19 Pharmacokinetics and Pharmacodynamics of Antiinfective Agents Short View Summary Pharmacokinetics Absorption Distribution Metabolism and Biotransformation Elimination Pharmacodynamics Antimicrobial Potency Pharmacodynamics Indices Methodology for Study of Pharmacodynamics Effects of Antiinfective Agents In Vitro Models Animal Models Clinical Trials Concentration-Dependent Killing Agents Time-Dependent Killing Agents Postantibiotic Effect Applied Clinical Pharmacokinetics and Pharmacodynamics Higher-Dose Extended-Interval Dosing Continuous-Infusion and Extended-Infusion Regimens Dose-Refinement Considerations Antiretroviral Pharmacodynamics Defined Exposure (PK)-Response (PD) Relationships by Class Protease inhibitors. Nonnucleoside reverse transcriptase inhibitors. Integrase strand transfer inhibitors. Entry inhibitors. Nucleoside reverse transcriptase inhibitors. Antiretroviral Therapeutic Drug Monitoring Alternative PK-PD Indices for Antiretroviral Therapy Pharmacodynamics for Other Antiviral Drugs Conclusions Key References References 20 Penicillins and β-Lactamase Inhibitors Short View Summary Penicillins Chemistry Mechanism of Action Resistance Mechanisms Classification Pharmacologic Properties Untoward Reactions Clinical Use Prophylactic Use Properties of Individual Penicillins Natural Penicillins Penicillin G Penicillin V Penicillinase-Resistant Penicillins Methicillin Nafcillin Isoxazolyl Penicillins Aminopenicillins Ampicillin Amoxicillin Carboxypenicillins Ureidopenicillins β-Lactamase Inhibitors and Inhibitor Combinations Clavulanic Acid Pharmacology Adverse Reactions Amoxicillin-Clavulanate Sulbactam Pharmacology Adverse Reactions Clinical Use Tazobactam Pharmacology Adverse Reactions Piperacillin-Tazobactam Clinical Use Ceftolozane-Tazobactam Avibactam Pharmacology Adverse Reactions Clinical Use Vaborbactam Pharmacology Adverse Reactions Clinical Use Key References References 21 Cephalosporins Chemistry Classification Mechanism of Action Spectrum of Activity Mechanisms of Resistance Pharmacologic Properties Adverse Reactions and Toxicities Major Clinical Uses of Cephalosporin Antibiotics First-Generation Cephalosporins Second-Generation Cephalosporins Third-Generation Cephalosporins Fourth-Generation Cephalosporins Fifth-Generation Cephalosporins (MRSA-Active Cephalosporins) Cephalosporin and β-Lactamase Inhibitor Combinations Key References References 22 Ertapenem, Imipenem, Meropenem, Doripenem, and Aztreonam Short View Summary Carbapenems Chemistry Mechanism of Action Resistance Carbapenem-Resistant Enterobacteriaceae Antibacterial Activity Pharmacology Adverse Reactions Clinical Use Monobactams Key References References 23 Antibiotic Allergy Pathophysiology Approach to a Patient With an Antibiotic Allergy Information to Be Obtained When Taking a History of Antibiotic Allergy Clinical Manifestations Immediate (Immunoglobulin E–Mediated or Pseudoallergic) Drug Reactions Nonimmediate Drug Reactions Drug Rash With Eosinophilia and Systemic Symptoms Diagnosis and Management of Antibiotic Allergy Tests for Immunoglobulin E–Mediated Immediate Reactions Skin Testing: Prick and Intradermal Tests In vitro Tests Drug Challenge (Drug Provocation Tests) Skin and in vitro Tests for Nonimmediate Reactions Skin Testing: Delayed Intradermal and Patch Tests In vitro Tests Procedures to Induce Temporary Drug Tolerance Drug Desensitization “Treating Through” Antibiotic-Associated Exanthems Drug Allergy to Specific Antimicrobial Agents β-Lactams Penicillins Epidemiology Evaluation of Penicillin Allergy as Part of Antimicrobial Stewardship Pathophysiology Clinical Manifestations Diagnosis Desensitization Cephalosporins Pathophysiology Clinical Manifestations Diagnosis Desensitization Carbapenems Monobactams Cross-Reactivity Among β-Lactams Sulfonamides Pathophysiology Clinical Manifestations Diagnosis Treatment Vancomycin Fluoroquinolones Macrolides Aminoglycosides Antibiotic Allergy and Antimicrobial Stewardship Multiple Drug Intolerance Syndrome Key References References 24 Fusidic Acid Short View Summary Structure and Mechanism of Action Antimicrobial Activity Resistance Administration and Dosing Pharmacokinetics and Pharmacodynamics Adverse Reactions Clinical Uses Key References References 25 Aminoglycosides Short View Summary Chemistry Mechanisms of Action Mechanisms of Resistance Antimicrobial Activity Clinical Pharmacology Nephrotoxicity Experimental Nephrotoxicity Clinical Nephrotoxicity Ototoxicity Cochlear Toxicity Vestibular Toxicity Neuromuscular Blockade Clinical Indications Bacteremia Pneumonia Intraabdominal Infections Urinary Tract Infections Cystic Fibrosis Prophylaxis Spectinomycin and Gonorrhea Aminoglycosides in Orthopedic Surgery Key References References 26 Tetracyclines, Glycylcyclines, and Chloramphenicol Short View Summary Tetracyclines Historical Overview and Classification Structure and Mechanism of Action Pharmacology Administration and Dosing Tetracycline Doxycycline Minocycline Absorption and Bioavailability Drug Distribution Drug Elimination Antimicrobial Activity Gram-Positive Bacteria Gram-Negative Bacteria Atypical Bacteria Spirochetes and Rickettsiae Mycobacteria and Nocardia Parasites Clinical Uses General Respiratory Tract Infections Gastrointestinal Tract Infections Genitourinary Tract Infections Spirochetal Infections Malaria Treatment and Chemoprophylaxis Other Infections Acne Vulgaris Antiinflammatory Uses Bioterrorism Prophylaxis Mechanism of Resistance Adverse Reactions General Gastrointestinal Side Effects Photosensitivity and Hyperpigmentation Teeth and Bone Hepatotoxicity Nephrotoxicity Neurotoxicity Hypersensitivity Reactions Teratogenicity Drug and Food Interactions Glycylcyclines Tigecycline Structure and Mechanism of Action Pharmacology Administration and Dosing Absorption and Bioavailability Drug Distribution Drug Elimination Antimicrobial Activity Gram-Positive Bacteria Gram-Negative Bacteria Anaerobic Bacteria Atypical Bacteria Mycobacterium and Nocardia Clinical Uses Skin and Skin Structure Infections Intraabdominal Infections Respiratory Tract Infections Other Uses Mechanism of Resistance Adverse Reactions Gastrointestinal Side Effects Hepatotoxicity and Pancreatitis Other Side Effects Increased Mortality Drug Interactions New Drug Approvals: Eravacycline and Omadacycline Chloramphenicol Structure and Mechanism of Action Pharmacology Administration and Dosage Absorption and Bioavailability Drug Distribution Drug Elimination Antimicrobial Activity Gram-Positive Bacteria Gram-Negative Bacteria Anaerobic Bacteria Other Organisms Clinical Uses Bacterial Meningitis and Brain Abscess Salmonella Infections Other Infections Mechanism of Resistance Adverse Reactions Hematologic Toxicity Bone Marrow Suppression Aplastic Anemia Gray Baby Syndrome Optic Neuritis and Neurologic Side Effects Other Reactions Drug Interactions Acknowledgment Key References References 27 Rifamycins Short View Summary Structure and Mechanism of Action Mechanisms of Resistance Shared Properties of the Rifamycins Rifampin Pharmacokinetics Adverse Reactions Antimicrobial Activity Rifabutin Pharmacokinetics Adverse Reactions Antimicrobial Activity Rifapentine Pharmacokinetics Adverse Effects Antimicrobial Activity Rifaximin Pharmacokinetics Adverse Effects Antimicrobial Activity Immune-Modulating Effects of Rifampin Rifamycins for the Treatment of Tuberculosis Rifamycins for Treatment of Latent Tuberculosis Infection Rifamycins for Nontuberculous Mycobacterial Infections Mycobacterium leprae Mycobacterium avium-intracellulare Complex Mycobacterium kansasii Other Nontuberculous Mycobacteria Rifamycins for Nontuberculous Mycobacterial Infections Staphylococcal Infections Staphylococcal Biofilms: Foreign-Body Infections and the Role of Rifampin Vancomycin-Intermediate and Vancomycin-Resistant Staphylococcus aureus and Rifampin Prosthetic Joint Infections Osteomyelitis Central Nervous System Infections Infections Caused by Other Bacteria Streptococcus pneumoniae Enterococci Legionella Rhodococcus Multidrug-Resistant Gram-Negative Bacilli Brucella Bartonella Fungal Infections Second-Line Indications for Rifamycins Chemoprophylaxis Novel and Future Indications for Rifampin Rifaximin: a Selective Gastrointestinal Rifamycin Rifalazil Rifamycins in Development Key References References 28 Metronidazole Short View Summary History Mechanism of Action Spectrum of Activity Effects on the Human Microbiome Pharmacology Adverse Effects, Contraindications, and Precautions Contraindications Precautions Adverse Effects Mechanisms of Resistance Clinical Uses Parasitic Infections Trichomonas Dientamoeba Entamoeba Giardia Anaerobic Infections Clostridioides difficile Infection Helicobacter pylori Infection Other Therapeutic Uses Prophylactic Use Drug Interactions and Interference With Laboratory Tests Other Nitroimidazole Antimicrobials Key References References 29 Macrolides and Clindamycin Short View Summary Erythromycin Derivation, Chemistry, and Preparations Mechanisms of Action Mechanisms of Resistance Decreased Microbial Entry or Export of Drug Target Site Alterations Drug Inactivation Antimicrobial Activity Clinical Pharmacology Adverse Reactions Drug Interactions Uses of Erythromycin Azithromycin and Clarithromycin Derivation, Chemistry, and Preparations Mechanisms of Action and Resistance Antimicrobial Activity Clinical Pharmacology Adverse Reactions Drug Interactions Uses of Clarithromycin and Azithromycin Ketolides Lincomycin and Clindamycin Derivation, Chemistry, and Preparations Mechanism of Action Mechanisms of Resistance Antimicrobial Activity Clinical Pharmacology Adverse Reactions Drug Interactions Uses of Clindamycin Acknowledgments Key References References 30 Glycopeptides (Vancomycin and Teicoplanin) and Lipoglycopeptides (Telavancin, Oritavancin, and Dalbavancin) Short View Summary Glycopeptides Vancomycin Structure and Mechanism of Action Antimicrobial Activity Mechanisms of Resistance Enterococci Staphylococcus aureus Heteroresistant vancomycin-intermediate Staphylococcus aureus (hVISA)/VISA. Mechanisms of decreased susceptibility to vancomycin. Laboratory detection of hVISA strains. Clinical impact of strains with increased vancomycin minimal inhibitory concentration. Vancomycin-resistant Staphylococcus aureus. Coagulase-Negative Staphylococci Other Gram-Positive Bacteria Clinical Pharmacodynamics and Pharmacokinetics Distribution Excretion Administration Dosing in Renal Insufficiency Adverse Reactions Drug Interactions Clinical Uses Skin and Soft Tissue Infections Bacteremia and Endocarditis Meningitis and Ventriculitis Pneumonia Osteomyelitis Pseudomembranous Colitis Febrile Neutropenia Prophylaxis Other Uses Teicoplanin Antimicrobial Activity and Resistance Clinical Pharmacokinetics Adverse Events Clinical Uses Lipoglycopeptides Telavancin Structure and Mechanism of Action Antimicrobial Activity and Resistance Clinical Pharmacodynamics and Pharmacokinetics Efficacy of Telavancin in Animal Models Adverse Reactions Clinical Uses Skin and Soft Tissue Infections Hospital-Acquired Pneumonia Other Clinical Uses Dalbavancin Structure and Mechanism of Action Antimicrobial Activity and Resistance Clinical Pharmacodynamics and Pharmacokinetics Adverse Reactions Clinical Uses Oritavancin Structure and Mechanism of Action Antimicrobial Activity and Resistance Clinical Pharmacokinetics and Pharmacodynamics Adverse Reactions and Drug Interactions Clinical Uses Conclusions Key References References 31 Daptomycin and Quinupristin-Dalfopristin Short View Summary Daptomycin Mechanism of Action Antimicrobial Activity Resistance Clinical Pharmacokinetics and Pharmacodynamics Distribution and Elimination Pharmacodynamics Drug Dosage and Administration Adverse Reactions and Drug Interactions Clinical Uses Skin and Soft Tissue Infections Staphylococcus aureus Bacteremia and Right-Sided Endocarditis Osteoarticular Infections Caused by Staphylococci Enterococcal Infections Other Clinical Uses Streptogramins Quinupristin-Dalfopristin Mechanism of Action Antimicrobial Activity Resistance Clinical Pharmacodynamics and Pharmacokinetics Distribution and Elimination Administration and Dosing Adverse Events and Drug Interactions Clinical Uses Key References References 32 Polymyxins (Polymyxin B and Colistin) Short View Summary Structure, Source, and Available Preparations Mechanism of Action Antimicrobial Activity Pharmacokinetics Colistimethate Sodium Polymyxin B Pharmacodynamics Toxicity Clinical Use Key References References 33 Linezolid, Tedizolid, and Other Oxazolidinones Short View Summary Chemical Structure Mechanism of Action Antimicrobial Activity General Considerations Activity Against Gram-Positive Organisms Activity Against Higher Order Bacteria Activity Against Mycobacterium spp. Activity Against Other Organisms Resistance Pharmacology Linezolid Tedizolid Clinical Use Linezolid Tedizolid Staphylococcus aureus Including Methicillin-Resistant S. aureus Linezolid Tedizolid Coagulase-Negative Staphylococci Vancomycin-Resistant Enterococci Tedizolid Streptococci Including Streptococcus pneumoniae Linezolid Tedizolid Mycobacterium Including Mycobacterium tuberculosis Linezolid Tedizolid Nocardia spp. Linezolid Tedizolid Untoward Reactions Hematologic Toxicity Monoamine Oxidase Inhibition Adverse Effects Associated With Mitochondrial Toxicity Neuropathy Lactic Acidosis Miscellaneous Untoward Reactions Linezolid Versus Tedizolid Other Oxazolidinones Key References References 34 Sulfonamides and Trimethoprim; Trimethoprim-Sulfamethoxazole Short View Summary Sulfonamides Structure Derivation and Nomenclature Short-Acting or Medium-Acting Sulfonamides Long-Acting Sulfonamides Sulfonamides Limited to the Gastrointestinal Tract Topical Sulfonamides Mechanisms of Action Antimicrobial Activity in vitro Antimicrobial Resistance Pharmacology Routes of Administration Absorption Distribution Metabolism and Excretion Protein Binding and Blood or Tissue Levels Toxicity and Adverse Reactions Drug Interactions Major Clinical Uses Trimethoprim Structure and Derivation Mechanism of Action Antimicrobial Activity Resistance to Trimethoprim Pharmacology Routes of Administration Distribution Metabolism and Excretion Clinical Use Trimethoprim-Sulfamethoxazole Mechanism of Action and Antimicrobial Activity Trimethoprim-Sulfamethoxazole Resistance Metabolism and Excretion Toxicity and Side Effects Dermatologic Reactions Hematologic Reactions Renal and Electrolyte Abnormalities Gastroenterologic and Hepatic Effects Neurologic and Psychiatric Effects Miscellaneous Adverse Effects Drug Interactions Trimethoprim Plus Other Antimicrobial Agents Clinical Uses of Trimethoprim-Sulfamethoxazole Urinary Tract Infections Respiratory Tract Infections Gastrointestinal Infections Skin, Soft Tissue, and Bone Infections Sexually Transmitted Diseases Other Infections Pneumocystis jiroveci Infections in HIV-Infected Patients Trimethoprim-Sulfamethoxazole Use in Other Immunocompromised Patients Trimethoprim Use in Pregnancy Iclaprim Key References References 35 Quinolones Short View Summary Chemical Structures Mechanism of Action Mechanisms of Acquired Bacterial Resistance Antimicrobial Activity Pharmacology Absorption Distribution in Tissues Elimination Dosage Adjustments in Renal and Hepatic Insufficiency Interactions With Other Drugs Clinical Uses Urinary Tract Infections Prostatitis Sexually Transmitted Diseases Gastrointestinal and Abdominal Infections Respiratory Tract Infections Bone and Joint Infections Skin and Soft Tissue Infections Other Uses Problems With Quinolone Resistance During Clinical Use Adverse Effects Key References References 36 Unique Antibacterial Agents Short View Summary Multidrug-Resistant Bacteria Plazomicin (ACHN-490) Cefiderocol (S-649266) Meropenem-Vaborbactam (Vabomere) Fosfomycin (ZTI-01, Contepo): Intravenous Omadacycline (PTK 0796, Nuzyra) Eravacycline (TP-434, Xerava) Lefamulin (BC-3781) Iclaprim Overall Conclusions Acknowledgments References 37 Urinary Tract Agents Short View Summary Nitrofurantoin Mechanisms of Drug Action and Bacterial Resistance Spectrum of Activity Pharmacology Absorption Distribution Excretion Dosing Indications Acute Uncomplicated Cystitis Acute Pyelonephritis and Complicated Urinary Tract Infections Prophylaxis for Recurrent Urinary Tract Infections Adverse Effects Pulmonary Reactions Gastrointestinal Reactions Cutaneous Reactions Hepatic Reactions Hematologic Reactions Peripheral Neuropathy Systemic Inflammatory Response Syndrome Drug Interactions Use in Children and During Pregnancy Fosfomycin Mechanism of Action and Antimicrobial Activity Pharmacology Dosing Indications Acute Uncomplicated Cystitis Adverse Effects Use During Pregnancy Methenamine Mechanism of Action and Antimicrobial Activity Pharmacology Absorption and Distribution Factors Affecting Formaldehyde Concentrations in Urine Acidification of Urine During Methenamine Treatment Dosing Indications Adverse Effects Key References References 38 Topical Antibacterials Short View Summary General Uses of Topical Antibacterials Skin Disinfection Prophylaxis of Infection in Clean Wounds Prophylaxis of Recurrent Skin and Soft Tissue Infections Prophylaxis of Infection in Operative Wounds MRSA Decolonization Universal Decolonization Targeted Decolonization for Patients Who Screen Positive for Staphylococcus aureus Topical Skin Antisepsis Methods to Decrease Bioburden on Skin Prophylaxis of Vascular Catheter–Related Infections Prophylaxis of Peritoneal Dialysis Catheter Infections Prophylaxis of Hemodialysis Catheter Infections Prophylaxis of Health Care–Associated Infections Prophylaxis of Infection in Burn Wounds Treatment of Pyoderma Treatment of Erythrasma and Rosacea Treatment of Acne Vulgaris Elimination of Staphylococcus aureus Nasal Carriage Specific Topical Antibacterials Bacitracin Mechanism of Effects In Vitro Spectrum of Activity Clinical Uses Adverse Effects Neomycin Mechanism of Action In Vitro Spectrum of Activity Clinical Uses Adverse Effects Polymyxin B Mechanism of Action In Vitro Spectrum of Activity Clinical Uses Adverse Effects Mupirocin Structure and Mechanism of Action In Vitro Spectrum of Activity Pharmacokinetics Clinical Uses Adverse Effects Key References References 39 Antimycobacterial Agents Short View Summary First-Line Antituberculous Drugs Isoniazid Derivation and Structure Mechanism of Action Antimicrobial Activity and Resistance Pharmacology Adverse Reactions Hepatitis. Neurotoxicity. Hypersensitivity reactions. Miscellaneous adverse reactions. Overdose Significant Drug Interactions Usage Availability and Dosage Rifampin (see also Chapter 27) Derivation and Structure Mechanism of Action Antimicrobial Activity and Resistance Pharmacology Adverse Reactions Hepatitis. Effects on immune parameters. Hypersensitivity reactions. Miscellaneous adverse reactions. Significant Drug Interactions Usage Availability and Dosage Pyrazinamide Derivation and Structure Mechanism of Action Antimicrobial Activity and Resistance Pharmacology Adverse Reactions Significant Drug Interactions Usage Availability and Dosage Ethambutol Derivation and Structure Mechanism of Action Antimicrobial Activity and Resistance Pharmacology Adverse Reactions Significant Drug Interactions Usage Availability and Dosage Streptomycin Derivation, Structure, and Pharmacology Antimicrobial Activity and Resistance Adverse Reactions Significant Drug Interactions Usage Availability and Dosage Alternatives to Rifampin Rifabutin Derivation and Pharmacology Adverse Reactions Significant Drug Interactions Usage Rifapentine Derivation and Pharmacology Adverse Drug Reactions Significant Drug Interactions Usage Availability and Dosage Second-Line Antituberculous Drugs Quinolones (see Chapter 35) Mechanism of Action Antimicrobial Activity and Resistance Usage Adverse Reactions Significant Drug Reactions Linezolid (see Chapter 33) Capreomycin, Amikacin, and Kanamycin Capreomycin Antimicrobial Activity and Resistance Adverse Reactions Significant Drug Interactions Usage Availability and Dosage Amikacin Antimicrobial Activity and Resistance Adverse Reactions Usage Kanamycin Availability and Dosage Para-Aminosalicylic Acid Derivation, Structure, and Pharmacology Adverse Reactions Usage Availability and Dosage Cycloserine Derivation and Mechanism of Action Pharmacology Adverse Reactions Usage Availability and Dosage Ethionamide Derivation, Mechanism of Action, and Resistance Pharmacology Adverse Reactions Usage Availability and Dosage β-Lactams Amithiozone New Drugs for Tuberculosis World Health Organization Antituberculosis Drug Classification for Drug-Resistant Tuberculosis Therapeutic Drug Monitoring Coadministration of Antituberculosis Therapy and Human Immunodeficiency Virus Medications Major Drugs for Treatment of Nontuberculous Mycobacterial Infections (see Chapters 251 and 252) Macrolides (see Chapter 29) Antimicrobial Activity and Resistance Pharmacology Adverse Reactions Significant Drug Interactions Dosage Rifampin Antimicrobial Activity Pharmacology, Adverse Events, and Significant Drug Interactions Usage Rifabutin Antimicrobial Activity Pharmacology, Adverse Events, and Significant Drug Interactions Usage Aminoglycosides Ethambutol Less Frequently Used Miscellaneous Antimicrobial Agents for Treatment of Nontuberculous Mycobacteria Isoniazid Tetracyclines Sulfonamides Quinolones Linezolid β-Lactams Clofazimine Susceptibility Tests Drugs for Treatment of Hansen Disease (Leprosy) (see Chapter 250) Background Dapsone Derivation and Structure Mechanism of Action Antimicrobial Activity Pharmacology Adverse Reactions Usage Availability and Dosage Rifampin Mechanism of Action and Resistance Usage Clofazimine (Lamprene) Derivation and Structure Mechanism of Action and Antimicrobial Activity Pharmacology Adverse Reactions Usage Availability and Dosage Additional or Second-Line Drugs Thiacetazone (Amithiozone) Ethionamide and Protionamide Other Substituted Rifamycins Other Sulfones Acedapsone Sulfoxone Newer Agents Chemotherapy-Associated Reactions in Leprosy Key References References 40A Antifungal Agents General Features Mechanism of Action Spectrum of Activity and Mechanisms of Resistance Available Formulations Amphotericin B Deoxycholate Formulation Pharmacology Toxicity Nephrotoxicity Other Chronic Toxicity Acute Reactions Administration Dosage Lipid-Associated Formulations of Amphotericin B Pharmacology and Toxicity Amphotericin B Lipid Complex Liposomal Amphotericin B Comparison of Amphotericin B Deoxycholate and the Lipid-Associated Formulations of Amphotericin B Other Routes for Amphotericin B Key References References 40B Antifungal Drugs Short View Summary Mechanisms of Triazole Resistance Fluconazole (Diflucan) Formulations and Pharmacology Drug Interactions Side Effects Therapeutic Drug Monitoring Indications Candidiasis Cryptococcosis Other Mycoses Prophylaxis in Neutropenic Patients Prophylaxis in Acquired Immunodeficiency Syndrome Prophylaxis in Preterm Neonates Itraconazole (Sporanox) and Enhanced Bioavailability Suba-Itraconazole (Tolsura/Lozanoc) Formulations and Pharmacology Drug Interactions Side Effects Therapeutic Drug Monitoring Clinical Use Voriconazole (Vfend) Formulations and Pharmacology Drug Interactions Side Effects Therapeutic Drug Monitoring Clinical Use Aspergillosis Febrile Neutropenia Other Mycoses Posaconazole (Noxafil) Formulations and Pharmacology Drug Interactions Side Effects Therapeutic Drug Monitoring Clinical Use Prophylaxis in High-Risk Patients Other Mycoses Isavuconazole (Cresemba) Formulations and Pharmacology Drug Interactions Side Effects Therapeutic Drug Monitoring Aspergillosis and Mucormycosis Other Use Investigational Agents Acknowledgments Key References References 40C Antifungal Drugs Short View Summary Structure, Mechanism of Action, and Spectrum of Activity Pharmacology Susceptibility Testing in vitro Echinocandin Resistance Clinical Indications Candidiasis Aspergillosis Empirical Treatment of Febrile Neutropenia and Antifungal Prophylaxis New Agents: Rezafungin and Ibrexafungerp Key References References 40D Antifungal Drugs Short View Summary Pharmacology Antimicrobial Activity Resistance Pharmacokinetics Pharmacodynamics Dosing, Administration, and Monitoring Therapeutic Drug Monitoring Toxicity Gastrointestinal Myelosuppression Hepatotoxicity Key References References 41 Antimalarial Drugs Short View Summary Artemisinin Derivatives Structures of Artemisinin Compounds Pharmacokinetics and Dynamics Clinical Use Severe Malaria Resistance Toxicity Artemisinin Partner Drugs Lumefantrine Pharmacokinetics Clinical Use Toxicity Piperaquine Pharmacokinetics Clinical Use Resistance Toxicity Pyronaridine Pharmacokinetics Clinical Use Toxicity Amodiaquine Pharmacokinetics Clinical Use Toxicity Mefloquine Pharmacokinetics Clinical Use Resistance Toxicity Chloroquine Pharmacokinetics Clinical Use Resistance Toxicity Quinine and Quinidine Pharmacokinetics Clinical Use Quinine Resistance Quinine for Treatment of Babesiosis Toxicity 8-Aminoquinolines Primaquine Pharmacokinetics Clinical Use Radical Cure Reduction of Transmission Chemoprophylaxis Toxicity Tafenoquine Pharmacokinetics Clinical Use Toxicity Atovaquone Pharmacokinetics Clinical Use Resistance Toxicity Folate Antagonists Dihydrofolate Reductase Inhibitors Proguanil (Chloroguanide) Pharmacokinetics Pyrimethamine Pharmacokinetics Toxicity Trimethoprim Dihydropteroate Synthetase Inhibitors Sulfonamides Sulfadiazine and Sulfamethoxazole Sulfadoxine Pharmacokinetics Toxicity Sulfones Antibiotics With Antimalarial Activity Doxycycline and Tetracycline Macrolides Azithromycin Clindamycin Key References References 42 Drugs for Protozoal Infections Other Than Malaria Short View Summary Drugs for Leishmaniasis and Trypanosomiasis Amphotericin B Antimonials Triazoles Miltefosine Paromomycin Pentamidine Benznidazole Fexinidazole Eflornithine Melarsoprol Nifurtimox Suramin Nitazoxanide Diloxanide Nitroimidazoles Spiramycin Atovaquone Other Drugs Rarely Used to Treat Intestinal Protozoal Infections Key References References 43 Drugs for Helminths Short View Summary Benzimidazoles Albendazole Mebendazole Thiabendazole Triclabendazole Macrocyclic Lactones Ivermectin Moxidectin Diethylcarbamazine Piperazine Doxycycline Pyrantel and Oxantel Pamoate Levamisole Tribendimidine Praziquantel Oxamniquine Metrifonate Niclosamide Nitazoxanide Bithionol Key References References 44 Antiviral Agents Mechanisms of Action of Antiviral Agents Inhibition of Viral Nucleic Acid Synthesis Integrase Strand Inhibitors CAP-Dependent Endonuclease Inhibitor RNA Antisense Nucleotides Viral Entry Inhibition Protease Inhibition Inhibition of Virus Uncoating Inhibition of Virus Release Modifiers of Host Defenses Against Viruses Interferons Innate Immunity Stimulators Host Sialidases Determination of Sensitivity of Viruses to Antiviral Agents Quantitation of Virus (Virus Load) Resistance to Antiviral Agents Combinations of Antiviral Agents Pharmacodynamics References 45 Antiviral Drugs for Influenza and Other Respiratory Virus Infections Short View Summary Amantadine and Rimantadine Spectrum Mechanism of Action Resistance Pharmacokinetics Amantadine Rimantadine Interactions Toxicity Clinical Studies Influenza A Other Viruses DAS181 (Fludase) Favipiravir (T-705) Laninamivir Octanoate Spectrum Mechanism of Action Resistance Pharmacokinetics Toxicity Clinical Studies Oseltamivir Spectrum Mechanism of Action Resistance Pharmacokinetics Interactions Toxicity Clinical Studies Peramivir Spectrum Mechanism of Action Resistance Pharmacokinetics Interactions Toxicity Clinical Studies Ribavirin Spectrum Mechanism of Action Resistance Pharmacokinetics Toxicity Interactions Clinical Studies Respiratory Syncytial Virus Other Respiratory Viruses RSV604 Zanamivir Spectrum Resistance Pharmacokinetics Interactions Toxicity Clinical Studies Polymeric Zanamivir Conjugates Spectrum Mechanism of Action Resistance Pharmacokinetics Interactions and Toxicity Clinical Studies Baloxavir Marboxil Key References References 46 Antivirals Against Herpesviruses Acyclovir and Valacyclovir Spectrum Mechanism of Action Resistance Pharmacokinetics Interactions Toxicity Clinical Studies Herpes Simplex Virus Varicella-Zoster Virus Infections Cytomegalovirus Other Viruses Brivudin Cidofovir Spectrum Mechanism of Action Resistance Pharmacokinetics Interactions Toxicity Clinical Studies CMX-001 (Brincidofovir) Docosanol Famciclovir and Penciclovir Spectrum Mechanism of Action Resistance Pharmacokinetics Interactions Toxicity Clinical Studies Fomivirsen Foscarnet Spectrum Mechanism of Action Resistance Pharmacokinetics Interactions Toxicity Clinical Studies Ganciclovir and Valganciclovir Spectrum Mechanism of Action Resistance Pharmacokinetics Interactions Toxicity Clinical Studies Idoxuridine Letermovir (AIC246) Trifluridine Vidarabine Maribavir Helicase-Primase Inhibitors (Amenamevir, Pritelivir) Amenamevir (ASP2151) Pritelivir (AIC316) Tenofovir Key References References 47 Antiviral Drugs Against Hepatitis Viruses Short View Summary Hepatitis B Overview Adefovir Spectrum and Mechanism of Action Resistance Pharmacology/Pharmacokinetics Interactions Toxicity Clinical Studies Entecavir Spectrum and Mechanism of Action Resistance Pharmacology/Pharmacokinetics Interactions Toxicity Clinical Studies Interferons Lamivudine Spectrum and Mechanism of Action Resistance Toxicity Clinical Studies Telbivudine Spectrum and Mechanism of Action Resistance Pharmacology/Pharmacokinetics Interactions Toxicity Clinical Studies Tenofovir Disoproxil Fumarate Spectrum and Mechanism of Action Resistance Pharmacology/Pharmacokinetics Toxicity Clinical Studies in Hepatitis B Virus Infection Tenofovir Alafenamide Spectrum and Mechanism of Action Resistance Pharmacology/Pharmacokinetics Drug Interactions Toxicity Clinical Studies Other Agents of Potential Interest Emtricitabine Clevudine The Future Hepatitis C Overview Interferons Ribavirin Boceprevir Spectrum and Mechanism of Action Mechanism of Action Resistance Pharmacology/Pharmacokinetics Interactions Toxicity Clinical Studies Telaprevir Spectrum and Mechanism of Action Mechanism of Action Resistance Pharmacology/Pharmacokinetics Interactions Toxicity Clinical Studies Simeprevir Spectrum and Mechanism of Action Resistance Pharmacology/Pharmacokinetics Interactions Toxicity Clinical Studies Sofosbuvir Spectrum and Mechanism of Action Resistance Pharmacology/Pharmacokinetics Interactions Toxicity Clinical Studies Ledipasvir/Sofosbuvir (Harvoni) Spectrum and Mechanism of Action Resistance Pharmacology/Pharmacokinetics Drug Interaction Toxicity Clinical Studies Paritaprevir/Ritonavir/Ombitasvir Plus Dasabuvir (Viekira Pak) Spectrum and Mechanism of Action Resistance Pharmacology/Pharmacokinetics Interactions Toxicity Clinical Studies Paritaprevir/Ritonavir/Ombitasvir (Technivie) Elbasvir/Grazoprevir (Zepatier) Spectrum and Mechanism of Action Resistance Pharmacology/Pharmacokinetics Drug Interactions Toxicity Clinical Studies Daclatasvir (Daklinza) Spectrum and Mechanism of Action Resistance Pharmacology/Pharmacokinetics Drug Interactions Toxicity Clinical Studies Velpatasvir/Sofosbuvir (Epclusa) Spectrum and Mechanism of Action Resistance Pharmacology/Pharmacokinetics Drug Interactions Toxicity Clinical Studies Glecaprevir/Pibrentasvir (Mavyret) Spectrum and Mechanism of Action Resistance Pharmacology/Pharmacokinetics Drug Interactions Toxicity Clinical Studies Sofosbuvir/Velpatasvir/Voxilaprevir (Vosevi) Spectrum and Mechanism of Action Resistance Pharmacology/Pharmacokinetics Drug Interactions Toxicity Clinical Studies State of the Art Key References References 48 Miscellaneous Antiviral Agents (Interferons, Tecovirimat, Imiquimod, Pocapavir, Pleconaril) Short View Summary Interferons Classification Mechanisms of Action Pharmacokinetics Interactions Toxicity Clinical Studies Herpesviruses Human Immunodeficiency Virus Papillomavirus Respiratory Viruses Enteroviruses Tecovirimat Imiquimod and Resiquimod Pleconaril Pocapavir Key References References 49 Immunomodulators Short View Summary Colony-Stimulating Factors Granulocyte Colony-Stimulating Factor Adverse Effects of Granulocyte Colony-Stimulating Factor Granulocyte Transfusions Granulocyte-Macrophage Colony-Stimulating Factor Adverse Effects of Granulocyte-Macrophage Colony-Stimulating Factor Macrophage Colony-Stimulating Factor Interferons Interferon-α Interferon-β Interferon-γ Interleukins Interleukin-1 Interleukin-2 Interleukin-7 Interleukin-10 Interleukin-11 Interleukin-12 Thymic Hormones Immunoglobulins Monoclonal Antibodies Glucocorticosteroids Synthetic Compounds With Immunomodulatory Activity Cell-Based Immunomodulatory Therapy Immunomodulatory Therapy and Infectious Risks Key References References 50 Hyperbaric Oxygen Short View Summary Physiologic Effects in Experimental Models Modulation of Inflammation and Immune Function Angiogenesis and Improved Wound Healing Antibacterial Properties Activity of Antimicrobial Agents Administration Indications Diabetic Foot Ulcers Necrotizing Soft Tissue Infections Clostridial Myonecrosis (Gas Gangrene) Refractory Osteomyelitis Bacterial Intracranial Abscess Mucormycosis Side Effects and Complications Patient Selection and Evaluation Cost Controversy Certification in Hyperbaric Medicine Conclusions Key References References 51 Antimicrobial Stewardship Short View Summary Antimicrobial Stewardship Philosophy and Sociology of Antimicrobial Use Antimicrobial Stewardship Strategies Educational Strategies Antimicrobial Formulary Restriction Strategies Preauthorization Strategies Postprescription Review With Feedback Computer-Assisted Antimicrobial Stewardship Measuring Outcomes From Antimicrobial Stewardship Programs Clinical Outcomes Economic Outcomes Microbiologic Outcomes Antimicrobial Stewardship Program Structure and Implementation Acute-Care Hospitals and Long-Term Care Facilities Outpatient and Ambulatory Care The Future Acknowledgment Key References References 52 Designing and Interpreting Clinical Studies in Infectious Diseases Lexicon of Terms in Clinical Study Design and Analysis Types of Studies Controls in Clinical Studies Trial Hypotheses Types of Error in Clinical Trials Methods to Control Bias in Clinical Trials Types of Nonrandomized Studies Methods to Attempt to Control Selection Bias in Nonrandomized Studies Outcomes of Clinical Studies Analysis Populations Analysis of Study Results Overview History Defining Terms Choosing a Research Question and Defining Goals of a Study Types of Analytical Study Designs Comparison With a Control Group Types of Hypotheses Design of Noninferiority Trials Selection of Study Participants Minimizing Error in Studies Baseline Comparability Between Study Groups Outcome Assessments Analysis of Study Results Analysis of Populations Examining Baseline Comparability Calculating Differences Between Groups Examining the Evidence: P Values and Confidence Intervals Measurement of Harms Subgroup Analyses Examining the Conclusions Key References References 53 Outpatient Parenteral Antimicrobial Therapy The History and Growth of OPAT Patient Selection for OPAT OPAT in People Who Inject Drugs Alternate Options for OPAT Use of Oral Antibiotic Therapy Use of Long-Acting Parenteral Agents Programmatic Requirements Infectious Diseases Provider OPAT Pharmacist Infusion Nurse Support Antimicrobial Stewardship System for Data Management and Communication Antimicrobial Considerations Drug Characteristics and Regimens Methods of Infusion and Drug Delivery Laboratory Monitoring of Antibiotic Therapy OPAT Program Outcome Measurement Readmissions Complications of Vascular Access Devices Financial Analysis of OPAT Programs Patient Satisfaction Future of OPAT Key References References 54 Tables of Antiinfective Agent Pharmacology Dosage Guidelines Dosage Adjustment for Renal Impairment Dosage Adjustment for Hepatic Impairment Dosage Adjustment for Body Size (Obese and Underweight) Drug-Drug Interactions Suggested Readings II Major Clinical Syndromes A Fever 55 Temperature Regulation and the Pathogenesis of Fever Short View Summary Terminology Clinical Thermometry Anatomic Variability Physiologic Variables “Normal Body Temperature” Thermoregulation The Generation of Fever Acute-Phase Response Biologic Value of Fever Biologic Value of Fever: the Case of Sepsis Biologic Value of Hypothermia Antipyretic Therapy: General Considerations Antipyretic Therapy: the Case of Sepsis Antipyretic Therapy: Pharmacologic Agents Antipyretic Therapy: Physical Methods of Antipyresis Acknowledgment Key References References 56 Fever of Unknown Origin Short View Summary Terminology and Definitions Classic Fever of Unknown Origin Infants and Children Elderly Persons Returned Travelers Nosocomial (Health Care–Associated) Fever of Unknown Origin Postoperative Patients Intensive Care Unit Patients Stroke Patients Neutropenic (Immune-Deficient) Fever of Unknown Origin HIV-Related Fever of Unknown Origin Diagnosis History Verification of Fever and Fever Pattern Physical Examination Laboratory Investigations Imaging Studies Invasive Diagnostic Procedures Molecular Genetic Testing Therapy Therapeutic Trials Management Prognosis Acknowledgement Key References References 57 The Acutely Ill Patient With Fever and Rash Short View Summary Approach to the Patient Pathogenesis of Rash Differential Diagnosis in Rash Characteristics of the Lesion Maculopapular Rash Nodular Lesions Diffuse Erythema Vesiculobullous Eruptions Petechial and Purpuric Eruptions Enanthems Neutrophilic Dermatoses, Including Sweet Syndrome Pathogens or Infectious Conditions Strongly Associated With Rash Sepsis Neisseria meningitidis Infection Pseudomonas Infection Bacterial Endocarditis Infections Due to Staphylococcus aureus and Streptococcus pyogenes Staphylococcal Scalded Skin Syndrome Staphylococcal Toxic Shock Syndrome Streptococcal Infections Rickettsial Infections Ehrlichia and Anaplasma Species Borrelia burgdorferi Infection Syphilis Candidiasis Measles New and Emerging Infectious Diseases Dengue, Chikungunya, and Zika Viruses Viral Hemorrhagic Fever Bacterial Diseases Due to Bartonella Species Orthopoxviruses Skin Lesions in Immunocompromised Patients Key References References B Upper Respiratory Tract Infections 58 The Common Cold Short View Summary Etiology Epidemiology Transmission Predisposing Factors Immunity Clinical Manifestations Pathogenesis Differential Diagnosis Complications Therapy Symptomatic Therapy Homeopathic Remedies Antiviral Therapy Hand Hygiene Key References References 59 Pharyngitis Short View Summary Definition Etiology Epidemiology Pathogenesis Microbiology Group A Streptococcus Non–group A Streptococcus Fusobacterium necrophorum Arcanobacterium haemolyticum Corynebacterium diphtheriae Neisseria gonorrhoeae Atypical Bacteria Epstein-Barr Virus Human Immunodeficiency Virus Enteroviruses Adenovirus Herpes Simplex Virus Diagnosis Culture for Group A Streptococci Rapid Antigen Detection Test Other Diagnostic Tests Therapy Complications Key References References 60 Acute Laryngitis Short View Summary Definition Epidemiology Microbiology Diagnosis and Therapy Complications Key References References 61 Otitis Externa, Otitis Media, and Mastoiditis Short View Summary Otitis Externa Pathogenesis Clinical Manifestations and Management Otitis Media Epidemiology Pathogenesis Microbiology Bacteria. Viruses Mycoplasma, Chlamydia, and Unusual Organisms Immunology Diagnosis and Clinical Course Management Acute Otitis Media Systemic and Topical Treatment of Otalgia Antibiotic Therapy Versus Observation Selection of Antimicrobial Agents Treatment of Otitis Media With Effusion Surgical Management Prevention of Acute Otitis Media Chemoprophylaxis Pneumococcal Vaccines Respiratory Virus Vaccines Additional Complications of Acute Otitis Media Mastoiditis Clinical Manifestations Diagnosis Management Key References References 62 Sinusitis Short View Summary Anatomy and Physiology of the Paranasal Sinuses Pathogenesis Microbiology Chronic Sinusitis Epidemiology Clinical Manifestations Diagnosis of Sinusitis Clinical Diagnosis Imaging Therapy Antimicrobial Adjunctive Treatment Corticosteroids Antihistamines/Decongestants Saline Sinus Surgery Complications Prevention Key References References 63 Epiglottitis Short View Summary Epidemiology and Etiology Clinical Manifestations Diagnosis Differential Diagnosis Therapy Initial Management Antibiotic Therapy Prevention Key References References 64 Infections of the Oral Cavity, Neck, and Head Short View Summary Microbiologic Considerations Unique Niches of the Indigenous Oral Microbiota Microbial Specificity in Odontogenic Infections Pathogenetic Mechanisms Mucosal Immunity of the Oral Cavity Anatomic Considerations Clinical Manifestations and Management Orofacial Odontogenic Infections Dentoalveolar Infections Gingivitis and Periodontal Infections Gingivitis Periodontitis Periodontal Abscess Pericoronitis Deep Fascial Space Infections Space Infections Around the Face Masticator spaces. Buccal, canine, and parotid spaces. Suprahyoid Space Infections Submandibular and sublingual spaces. Ludwig angina. Lateral pharyngeal space. Infrahyoid Space Infections Retropharygeal and danger spaces. Pretracheal space. Complications of Odontogenic Infections Suppurative Jugular Thrombophlebitis (Lemierre Syndrome) and Carotid Artery Erosion Septic Cavernous Sinus Thrombosis Maxillary Sinusitis Osteomyelitis of the Jaws Association With Cardiovascular Risk Orofacial Nonodontogenic Infections Infections of the Oral Mucosa Noma (Gangrenous Stomatitis) Aphthous Stomatitis Mucositis and Stomatitis in the Severely Immunocompromised Patient Infections of the Salivary Gland Suppurative Parotitis Chronic Bacterial Parotitis Viral Parotitis Miscellaneous Infections of the Neck and Head Suppurative Cervical Adenitis Infected Embryologic Cysts Suppurative Thyroiditis Infections from Bites, Irradiation, and Surgical Wounds Human and Animal Bites Irradiation and Postsurgical Wounds Diagnostic Approaches Microbiologic Investigation Imaging Techniques for the Localization of Infection Therapeutic Considerations Dental Caries and Periodontitis Suppurative Soft Tissue Infections Osteomyelitis Key References References C Pleuropulmonary and Bronchial Infections 65 Acute Bronchitis Short View Summary Microbial Etiology Pathogenesis Clinical Manifestations Diagnosis Therapy Prevention Key References References 66 Acute Exacerbations of Chronic Obstructive Pulmonary Disease Short View Summary Epidemiology Acute Exacerbation of Chronic Obstructive Pulmonary Disease Clinical Presentation Diagnosis Acute Exacerbation of Chronic Obstructive Pulmonary Disease Radiology Pathophysiology Mucosal Inflammation Microbes in Stable Chronic Obstructive Pulmonary Disease Microbes in Acute Exacerbation of Chronic Obstructive Pulmonary Disease Treatment Nonantimicrobial Treatment of Steady-State Chronic Obstructive Pulmonary Disease Nonantimicrobial Treatment of Acute Exacerbation of Chronic Obstructive Pulmonary Disease Antibiotic Treatment of Acute Exacerbation of Chronic Obstructive Pulmonary Disease Rationale for Antibiotics Whom to Treat Choice of Antibiotic Duration of Antibiotic Treatment Treatment of Viral Infection Preventions of Acute Exacerbations of Chronic Obstructive Pulmonary Disease Antibiotic Prophylaxis in Steady-State Chronic Obstructive Pulmonary Disease Vaccination Key References References 67 Acute Pneumonia Short View Summary Host Defenses and Pathogenesis Pulmonary Defense Systems Impairment of Pulmonary Defenses Clinical Evaluation History Physical Examination Diagnostic Testing Sputum Examination and Examination of Other Respiratory Tract Samples Fiberoptic Bronchoscopy Other Techniques Lung Biopsy Examination of Pleural Effusions Blood Culture, Serologic Studies, and Urine Studies, Including Antigen Detection Radiologic Examination Pneumonia Syndromes Acute Community-Acquired Pneumonia Community-Acquired Pneumonia in the Older Adult Severe Community-Acquired Pneumonia Health Care–Associated Pneumonia “Atypical” Pneumonia Pathogens Pneumonia in the Setting of Aspiration Eosinophilic Pneumonias Hospital-Acquired Pneumonia Pneumonia in the Immunosuppressed Host Management and Therapy of Pneumonia Antimicrobial Therapy Timing of Antibiotics Duration of Treatment and Use of Clinical Practice Guidelines Adjunctive Therapy Prevention of Pneumonia Key References References 68 Pleural Effusion and Empyema Short View Summary Physiology and Staging Noninfectious Effusion and Empyema Outcomes of Effusion and Empyema Microbiology Tuberculosis Other Bacteria Viruses Mycobacteria Other Than Tuberculosis Fungi Parasites Nematodes Cestodes Trematodes Other Parasites Diagnosis Fluid Analysis Treatment Key References References 69 Bacterial Lung Abscess Short View Summary Definition Pathophysiology Epidemiology Clinical Presentation Microbiology Diagnosis Therapy Duration of Therapy Surgical Intervention Response to Therapy and Prognosis Prevention Key References References 70 Chronic Pneumonia Short View Summary Causes Epidemiology Age, Gender, and Race Occupation and Hobbies Residence and Travel Contacts, Habits, and Drugs Underlying Disease Clinical Features Symptoms Signs Diagnostic Procedures Initial Laboratory Studies Additional Studies Chest Radiographic Studies Patients With Radiographic Evidence of Localized Infiltrates or Cavitation Invasive Procedures Patients With Radiographic Evidence of Diffuse Pulmonary Infiltration and Fibrosis Therapy Antimicrobial Agents Corticosteroids Bronchoscopy and Surgery Key References References 71 Cystic Fibrosis Short View Summary Clinical Disease Pathogenesis of Cystic Fibrosis–Related Lung Disease The Cystic Fibrosis Microbiome Major Cystic Fibrosis Pathogens Staphylococcus aureus Methicillin-Resistant Staphylococcus aureus Pseudomonas aeruginosa Burkholderia cepacia Complex Other Bacteria Nontuberculous Mycobacteria Respiratory Viruses Fungal Disease Treatment (Table 71.1) Antimicrobial Treatment Azithromycin Inhaled Antibiotics Cystic Fibrosis–Specific Antibiotic Treatment Approaches Non–Antibacterial-Based Treatments Restoring CFTR Function Infection Control Lung Transplantation Future Directions Key References References D Urinary Tract Infections 72 Urinary Tract Infections Short View Summary Terminology Pathologic Characteristics Acute Pyelonephritis Chronic Pyelonephritis (Chronic Interstitial Nephritis) Papillary Necrosis Caused by Infection Pathogenesis of Urinary Tract Infection Ascending Route Hematogenous Route Urovirulence in Bacteria Adhesins Fimbriae P Fimbriae Type I Fimbriae Other Adhesins Expression and Selection of Virulence Factors Other Virulence Factors of Uropathogenic E. coli Host Factors in Urinary Tract Infections Host Defense of the Urinary Tract Innate Immunity Urine and Bladder Defenses Adherence and Colonization Humoral and Cellular Immunity Genetic Factors Structural Abnormalities Epidemiology and Natural History of Urinary Tract Infection77 Infecting Organisms Asymptomatic Bacteriuria Versus Symptomatic Infection Urinary Tract Infection in Children Urinary Tract Infection in Adults Urinary Tract Infection in the Elderly Urinary Tract Infection in Other Conditions Infection in the Obstructed Kidney After Urologic Treatment of Hydronephrosis Infections in Polycystic Kidneys Clinical Manifestations Symptoms Alterations in Renal Function Diagnosis Presumptive Diagnosis of Urinary Tract Infection Diagnosis of Urinary Tract Infection by Culture General Considerations Urinary Tract Infection With Low Numbers of Organisms Localization of Site of Infection Management of Urinary Tract Infection General Considerations Nonantimicrobial Therapy Prevention of Urinary Tract Infection Principles of Antimicrobial Therapy Serum, Tissue, and Urine Concentrations of Antimicrobial Agents Response to Therapy Bacteriologic Cure Bacteriologic Persistence Bacteriologic Relapse Reinfection Considerations in Choice of Therapy Classification and Antimicrobial Therapy for Different Groups Infection in Children Acute Uncomplicated Pyelonephritis in Women Oral Therapy Parenteral Therapy Uncomplicated Cystitis in Women Complicated Urinary Tract Infection, Including Infection in Men Asymptomatic Bacteriuria Relapsing Urinary Tract Infection Reinfection of the Urinary Tract and Antimicrobial Prophylaxis Fungal Infections Urinary Tract Infection in Pregnancy Physiologic Alterations in the Urinary Tract Epidemiology Management of Bacteriuria of Pregnancy Perinephric Abscess and Intrarenal Abscess Perinephric Abscess Intrarenal Abscess Diagnosis and Therapy Imaging Studies Surgical Management Summary of Treatment Approaches Key References References E Sepsis 73 Sepsis and Septic Shock Short View Summary Definition Clinical Signs and Symptoms Source of Sepsis Organ Failure in Sepsis Acute Lung Injury Cardiovascular Dysfunction Renal Dysfunction Dysfunction of Brain, Peripheral Nerves, and Muscles Coagulopathy and Disseminated Intravascular Coagulation Gastrointestinal Tract and Hepatic Injury Epidemiology Incidence Mortality Trends in Time: Incidence and Mortality Risk Factors Microbiology Main Causative Agents Virulence Factors of Bacteria Causing Sepsis Antimicrobial Resistance Trends in the Setting of Sepsis Pathogenesis Hyperinflammation Instigation of Inflammation Activation of the Complement System Activation of Coagulation and Vascular Endothelium Interaction Between Complement and Coagulation Systems Endothelial Dysfunction Neutrophil Extracellular Traps Platelets Antiinflammatory Mechanisms and Immunosuppression Suppression of Innate Immune Cell Functions Suppression of Adaptive Immune Cell Functions Diagnosis Hematologic and Biochemical Evaluation Pathogen Detection Diagnostic Imaging Host Response Biomarkers Therapy Surviving Sepsis Campaign Guidelines Empirical Antibiotic Therapy Immunomodulation Therapeutics That Seek to Inhibit Hyperinflammation Therapeutics That Seek to Stimulate the Immune System Mesenchymal Stem Cells Prognosis Future Perspectives Key References References F Intraabdominal Infections 74 Peritonitis and Intraperitoneal Abscesses Short View Summary Anatomy and Physiology Peritonitis Primary Peritonitis Etiology Bacteriologic Characteristics Pathogenesis Clinical Manifestations Laboratory Findings Diagnosis Prognosis Therapy Prevention Secondary and Tertiary Peritonitis Etiology Microbiologic Characteristics Pathogenesis Pathophysiologic Responses Local Response Systemic Response Gastrointestinal. Cardiovascular. Respiratory. Renal. Metabolic. Clinical Manifestations Symptoms Physical Findings Diagnostic Studies Prognosis Therapy Antimicrobial Therapy Chloramphenicol. Clindamycin. Metronidazole. Tetracyclines. Cephalosporins. Penicillins. Carbapenems and aztreonam. Aminoglycosides. Fluoroquinolones. Tigecycline. Eravacycline. Pharmacodynamic Considerations Duration of antimicrobial therapy. Hyperbaric Oxygen Gastrointestinal Drainage Water and Electrolyte Administration Blood and Plasma Transfusion Respiratory Support Operative Approach Prevention Peritonitis During Peritoneal Dialysis Long-Term Peritoneal Dialysis Source of Infection and Risk Factors Microbiology Diagnosis Treatment and Prognosis Catheter Removal and Prevention Acute Peritoneal Dialysis Intraperitoneal Abscesses Etiology Bacteriologic Findings Pathogenesis Clinical Manifestations Diagnosis Prognosis Therapy Key References References 75 Infections of the Liver and Biliary System (Liver Abscess, Cholangitis, Cholecystitis) Short View Summary Liver Abscess Epidemiology/Etiology Amebic Liver Abscess Pyogenic Liver Abscess Pathogenesis and Pathophysiology Amebic Liver Abscess Pyogenic Liver Abscess Microbiology Amebic Liver Abscess Pyogenic Liver Abscess Epidemic Klebsiella pneumoniae Pyogenic Liver Abscess Clinical Manifestations Amebic Liver Abscess Pyogenic Liver Abscess Diagnosis Therapy Amebic Liver Abscess Pyogenic Liver Abscess Infection of the Biliary System Pathogenesis Cholecystitis Acalculous Cholecystitis Cholangitis Clinical Manifestations Diagnosis Imaging Studies Microbiology AIDS Cholangiopathy (AIDS-Related Sclerosing Cholangitis) Therapy Acute Cholecystitis Acute Cholangitis Key References References 76 Pancreatic Infection Short View Summary Infectious Causes of Acute Pancreatitis Pancreatitis and Human Immunodeficiency Virus Infection Infection Complicating Acute Pancreatitis Background Significance of Infection in Acute Pancreatitis Defining Pancreatic Infections Diagnosis of Pancreatic Infection Microbiology of Pancreatic Infection Management of Pancreatic Infection Prevention of Pancreatic Infection Early Enteral Feeding Selective Decontamination of the Digestive Tract Preemptive Systemic Antibiotic Therapy Additional Data Review Article Recommendations Guidelines Actual Practice Conclusions Key References References 77 Splenic Abscess Short View Summary Epidemiology Pathogenesis Microbiology Clinical Manifestations Diagnosis Ultrasonography Computed Tomography Magnetic Resonance Imaging Therapy Key References References 78 Appendicitis Short View Summary Epidemiology Pathogenesis Microbiology Clinical Manifestations Diagnosis Therapy Key References References 79 Diverticulitis and Neutropenic Enterocolitis Short View Summary Diverticulitis Epidemiology Pathogenesis Microbiology Clinical Manifestations Diagnosis Therapy Neutropenic Enterocolitis (Typhlitis) Pathogenesis Clinical Manifestations Diagnosis Therapy Key References References G Cardiovascular Infections 80 Endocarditis and Intravascular Infections Short View Summary Infective Endocarditis Epidemiology Age Health Care–Associated Infective Endocarditis Pattern of Valvular Involvement Predisposing Factors Pathogenesis and Pathophysiology Nonbacterial Thrombotic Endocarditis Hemodynamic Factors Transient Bacteremia Microorganism–Nonbacterial Thrombotic Endocarditis Interaction Viridans-Group Streptococcal Interactions With Platelets Adhesion to Nonbacterial Thrombotic Endocarditis by Other Organisms Pathogenesis of Staphylococcus aureus Infective Endocarditis Effect of Antibiotics on Development of Infective Endocarditis Platelets and the Pathogenesis of Infective Endocarditis Interactions Between Bacteria and the Growing Vegetation Immunopathologic Factors Pathologic Changes Heart Kidney Mycotic Aneurysms Central Nervous System Spleen Lung Skin Eye Clinical Manifestations Cardiac Murmurs Peripheral Manifestations of Infective Endocarditis Splenomegaly Musculoskeletal Manifestations Embolic Events Neurologic Manifestations Renal Manifestations Infective Endocarditis in Drug Addicts Laboratory Findings Special Diagnostic Tests Echocardiography Transesophageal Echocardiography Cardiac Catheterization Diagnostic Criteria Etiologic Agents Streptococci Enterococci Streptococcus pneumoniae β-Hemolytic Streptococci Gemella Aerococci Staphylococci Coagulase-Negative Staphylococci Gram-Negative Bacilli HACEK Group Bacteria (Haemophilus, Aggregatibacter [Formerly Actinobacillus spp.], Cardiobacterium, Eikenella, Kingella) Other Gram-Negative Bacteria Gram-Positive Bacilli Anaerobic Bacteria Other Bacteria Coxiella burnetii Chlamydia psittaci Tropheryma whipplei Brucella species Unusual Bacterial Causes of Infective Endocarditis Fungi Viruses Culture-Negative Endocarditis Polymicrobial Endocarditis Etiology of Infective Endocarditis in Injection Drug Users Therapy for Infective Endocarditis General Principles Tests Useful for Antimicrobial Treatment Monitoring Antimicrobial Therapy Penicillin-Sensitive Streptococcal Endocarditis Endocarditis Caused by Streptococci With Penicillin Minimal Inhibitory Concentration Greater Than 0.5 µg/mL or by Enterococci Alternatives to Full-Course Aminoglycoside Therapy for Enterococcal Infective Endocarditis Staphylococcal Endocarditis Daptomycin for Staphylococcal Infective Endocarditis Other Antibiotics for Staphylococcal Infective Endocarditis Therapy for Highly Resistant Staphylococci Treatment of S. aureus Bacteremia Without Proven Infective Endocarditis Coagulase-Negative Staphylococci Endocarditis Due to Enterobacteriaceae or Pseudomonas Species Endocarditis Due to Anaerobic Bacilli Pneumococcal, Gonococcal, and Meningococcal Endocarditis Fungal Endocarditis Q Fever Endocarditis Infective Endocarditis Due to Chlamydiae Culture-Negative Endocarditis Surgical Therapy Suppurative Thrombophlebitis Epidemiology Pathogenesis Pathologic Changes Clinical Manifestations Laboratory Findings Etiologic Agents Presumptive Therapy Prevention Infective Endarteritis and Mycotic Aneurysms Epidemiology Pathogenesis Pathologic Changes Clinical Manifestations Laboratory Findings Etiologic Agents Therapy Key References References 81 Prosthetic Valve Endocarditis Short View Summary Prosthetic Valves Mechanical Valves Bioprosthetic Valves Transcatheter Expandable Valves Epidemiology Prosthetic Valve Endocarditis After Transcatheter Valve Replacement Microbiology Early- and Late-Onset Prosthetic Valve Endocarditis Health Care–Associated Prosthetic Valve Endocarditis Community-Acquired Prosthetic Valve Endocarditis Outbreaks of Nontuberculous Mycobacterial Infections Pathogenesis Microbial Adherence Formation and Growth of Vegetations Persistence and Growth of Microorganisms Tissue Destruction and Invasion Pathology Clinical Presentation Diagnosis Echocardiography Nuclear Medicine Imaging Techniques Labeled Leukocyte Scintigraphy Positron Emission Tomography/ Computer Tomography Limitations of Positron Emission Tomography/Computer Tomography Identification of the Pathogen Blood Cultures Valve Culture Serologic Methods Broad-Range Polymerase Chain Reaction Based on the Bacterial 16S rRNA Gene Histology Antimicrobial Therapy Staphylococcal Prosthetic Valve Endocarditis Streptococcal Prosthetic Valve Endocarditis Enterococcal Prosthetic Valve Endocarditis HACEK Prosthetic Valve Endocarditis Diphtheroid Prosthetic Valve Endocarditis Enteric Gram-Negative Bacillary Prosthetic Valve Endocarditis Fungal Prosthetic Valve Endocarditis Prosthetic Valve Endocarditis Due to Nontuberculous Mycobacteria Culture-Negative Prosthetic Valve Endocarditis Surgical Intervention Indications for Surgical Intervention Severe Heart Failure Due to Prosthetic Valve Dysfunction Perivalvular Extension of Infection High-Grade Pathogens Multiple Emboli Timing of Surgery Timing of Surgery in Patients With Central Nervous System Embolism Surgical Treatment Outcome of Patients Treated Surgically for Prosthetic Valve Endocarditis Duration of Antimicrobial Therapy Postoperatively Anticoagulation Therapy Prevention Key References References 82 Infections of Nonvalvular Cardiovascular Devices Short View Summary Cardiovascular Implantable Electronic Devices Epidemiology of Cardiovascular Implantable Electronic Device Infections Pathogenesis of Cardiovascular Implantable Electronic Device Infections Risk Factors for Cardiovascular Implantable Electronic Device Infections Microbiology of Cardiovascular Implantable Electronic Device Infection Clinical Manifestations of Cardiovascular Implantable Electronic Device Infection Diagnosis of Cardiovascular Implantable Electronic Device (CIED) Infection Role of Echocardiography in Diagnosis of Cardiovascular Implantable Electronic Device Infection Complications of Cardiovascular Implantable Electronic Device Infection Management of Cardiovascular Implantable Electronic Device Infection Prevention Left Ventricular Assist Devices Epidemiology of Left Ventricular Assist Device Infections Pathogenesis of Left Ventricular Assist Device Infections Risk Factors for Left Ventricular Assist Device Infections Clinical Manifestations of Left Ventricular Assist Device Infections Microbiology of Left Ventricular Assist Device Infections Management of Left Ventricular Assist Device Infections Prevention Prosthetic Vascular Grafts Epidemiology of Prosthetic Vascular Graft Infection Pathogenesis of Prosthetic Vascular Graft Infection Risk Factors for Prosthetic Vascular Graft Infection Microbiology of Prosthetic Vascular Graft Infection Clinical Manifestations of Prosthetic Vascular Graft Infection Diagnosis of Prosthetic Vascular Graft Infection Management of Prosthetic Vascular Graft Infection Surgical Management of Extracavitary Prosthetic Vascular Graft Infection Antimicrobial Management of Extracavitary Prosthetic Vascular Graft Infection Surgical Management of Intraabdominal Prosthetic Vascular Graft Infection Antimicrobial Management of Intraabdominal Prosthetic Vascular Graft Infection Management of Intrathoracic Prosthetic Vascular Graft Infection Prevention Hemodialysis Prosthetic Vascular Grafts Epidemiology Clinical Manifestations Management Prevention Invasive Nonsurgical Cardiologic Procedures Epidemiology Risk Factors Clinical Manifestations Microbiology Treatment Prevention Coronary Artery Stents Peripheral Vascular Stents Epidemiology Diagnosis Management and Outcome Prevention Vascular Closure Devices Epidemiology and Clinical Manifestations Microbiology Management Prevention of Percutaneous Vascular Closure Device–Related Infection Intraaortic Balloon Pumps Vena Cava Filters Dacron Carotid Patches Clinical Manifestations Management Cardiac Suture Line Infections Clinical Manifestations Management of Cardiac Suture Line Infections Closure Device Treatment of Patent Ductus Arteriosus, Atrial Septal Defect, and Ventricular Septal Defect Key References References 83 Prevention of Infective Endocarditis Short View Summary Pathogenesis of Infective Endocarditis in the Context of Prevention Estimation of the Risk for Infective Endocarditis Procedures at Risk for Causing Infective Endocarditis Preexisting Cardiac Conditions Indirect Evidence Regarding the Risk for Infective Endocarditis Posed by Dental Procedures and the Efficacy of Prophylaxis Cohort Studies Case-Control Studies In Vitro Antibiotic Susceptibility Studies Experimental Infective Endocarditis Potential Interventions to Prevent Endocarditis Correction of Predisposing Cardiac Conditions Minimization of Portals of Entry for Microorganisms Prevention of Health Care–Associated Infections Administration of Systemic Antibiotics Evolution of Clinical Practice in Prevention of Infective Endocarditis Historical Trends Over 7 Decades Current Guidelines Timing, Dosage and Duration of Antibiotic Prophylaxis Cost-Benefit and Cost-Effectiveness Analyses Specific Issues in Prevention of Infective Endocarditis Prevention of Health Care–Associated Infective Endocarditis Prevention of Infective Endocarditis Due to the Implantation of Cardiac Implantable Electronic Devices Prevention of Infective Endocarditis Due to Valvuloplasty and Valve Replacement Prevention of Infective Endocarditis in Patients With Prosthetic Heart Valves Cardiac Assist Devices and Artificial Hearts Cardiac Transplantation Medical Diagnostic Procedures Invasive Procedures Involving Infected or Nonsterile Sites Prophylaxis of Infective Endocarditis for Children Anticoagulant Therapy Medicolegal Liability Issues New Horizons for Antibiotic Prophylaxis of Infective Endocarditis Oral Hygiene “Big Data” as a Vehicle to Assess the Usefulness of Infective Endocarditis Prevention Measures Novel Approaches Conclusion Key References References 84 Myocarditis and Pericarditis Short View Summary Myocarditis Etiologic Agents Nonviral Pathogens That Cause Myocarditis Pathology and Pathogenesis Clinical Manifestations Diagnosis Treatment Prevention Pericarditis Etiologic Agents Pathology, Pathogenesis, and Pathophysiology Clinical Manifestations Diagnosis Treatment Key References References 85 Mediastinitis Short View Summary Anatomic Considerations Acute Mediastinitis Epidemiology and Pathogenesis Mediastinitis Secondary to Esophageal Perforation Mediastinitis Secondary to Head and Neck Infections or From Other Sites Mediastinitis Secondary to Cardiothoracic Surgery Risk Factors for Mediastinitis Pathogenesis Bacteriology Clinical Manifestations and Diagnosis Mediastinitis Caused by Bacillus anthracis Cardiac Surgery–Related Mediastinitis Therapy Mediastinitis Due to Esophageal Perforation Mediastinitis Due to Head and Neck Infection Cardiac Surgery–Related Mediastinitis Prevention of Mediastinitis After Cardiac Surgery Complications and Prognosis Chronic/Fibrosing Mediastinitis Definition and Etiology Manifestations and Diagnosis Pathogenesis Treatment Key References References H Central Nervous System Infections 86 Approach to the Patient With Central Nervous System Infection Clinical Manifestations Meningitis Encephalitis Focal Central Nervous System Syndromes Lumbar Puncture Opening Pressure and Appearance Cell Count Glucose and Protein Other Cerebrospinal Fluid Tests Neuroimaging Studies Management Antimicrobial Therapy Surgical Therapy Adjunctive Therapy References 87 Acute Meningitis Short View Summary Defining Acute Meningitis Epidemiology and Etiology Viral Meningitis Enteroviruses Herpesviruses Arboviruses Other Viruses Bacterial Meningitis Overview of Bacterial Meningitis Haemophilus influenzae Neisseria meningitidis Streptococcus pneumoniae Listeria monocytogenes Streptococcus agalactiae (Group B Streptococcus) Aerobic Gram-Negative Bacilli Staphylococci Other Bacteria Spirochetal Meningitis Treponema pallidum Borrelia burgdorferi Protozoal and Helminthic Meningitis Amebas Angiostrongylus cantonensis Pathogenesis and Pathophysiology Viral Meningitis Initiation of Infection Viremia and Central Nervous System Invasion Virus Spread Within the Central Nervous System Bacterial Meningitis Mucosal Colonization and Systemic Invasion Intravascular Survival Meningeal Invasion Bacterial Survival Within the Subarachnoid Space Induction of Subarachnoid Space Inflammation Alterations of the Blood-Brain Barrier Cerebral Edema and Increased Intracranial Pressure Alterations in Cerebral Blood Flow Clinical Manifestations Viral Meningitis Enteroviruses Herpesviruses West Nile virus Mumps Virus Bacterial Meningitis Neonates, Infants, and Children Adults Older Adults Underlying Conditions Pathogen-Specific Findings Spirochetal Meningitis Treponema pallidum Neuroborreliosis Protozoal and Helminthic Meningitis Amebas Angiostrongylus cantonensis Diagnosis Viral Meningitis Cerebrospinal Fluid Examination Bacterial Meningitis Cerebrospinal Fluid Examination Differentiation of Bacterial From Viral Meningitis Radiography Spirochetal Meningitis Treponema pallidum Borrelia burgdorferi Protozoal and Helminthic Meningitis Amebas Angiostrongylus cantonensis Initial Management of Patients With Acute Meningitis Who Should Have a Lumbar Puncture? Who Should Undergo Cranial Computed Tomography Before Lumbar Puncture Empirical Therapy of Community-Acquired Acute Bacterial Meningitis in Adults Selecting the Right Antimicrobial Adjunctive Corticosteroids Experimental Data Clinical Studies of Corticosteroids in Infants and Children Clinical Studies of Corticosteroids in Adults Antimicrobial Therapy Viral Meningitis Bacterial Meningitis Principles of Therapy Specific Antimicrobial Therapy Haemophilus influenzae Neisseria meningitidis Streptococcus pneumoniae Listeria monocytogenes Streptococcus agalactiae Aerobic Gram-Negative Bacilli Staphylococci Other Bacteria Duration of Therapy Spirochetal Meningitis Treponema pallidum Borrelia burgdorferi Protozoal and Helminthic Meningitis Amebas Angiostrongylus cantonensis Adjunctive Therapy Viral Meningitis Bacterial Meningitis Antiinflammatory Agents Reduction of Intracranial Pressure Surgery Helminthic Meningitis Prevention Bacterial Meningitis Haemophilus influenzae Chemoprophylaxis Neisseria meningitidis Chemoprophylaxis Streptococcus pneumoniae Chemoprophylaxis Streptococcus agalactiae Chemoprophylaxis Basilar Skull Fracture Haemophilus influenzae Immunoprophylaxis Neisseria meningitidis Immunoprophylaxis Streptococcus pneumoniae Immunoprophylaxis Key References References 88 Chronic Meningitis Short View Summary Distinction From Other Chronic Central Nervous System Infections Myelitis, Myeloradiculitis, and Polyradiculitis Encephalitis Brain Abscess Chronic Meningitis Clinical Manifestations Diagnosis Physical Examination History Imaging Laboratory Findings Cerebrospinal Fluid Peripheral Blood Brain Biopsy Differential Diagnosis Cryptococcus Meningitis Coccidioides Meningitis Histoplasma Meningitis Candida Meningitis Sporothrix Meningitis Blastomyces Meningitis Phaeohyphomycotic Meningitis Other Molds Causing Meningitis Mycobacterium tuberculosis Meningitis Treponema pallidum Meningitis Borrelia burgdorferi Tropheryma whipplei Meningitis Nocardia and Actinomyces Meningitis Brucella Meningitis Amebic Granulomatous Meningitis Angiostrongylus cantonensis Meningitis Taenia solium Meningitis Enteroviral Meningitis Postneurosurgical Meningitis Sarcoidosis Meningitis Vogt-Koyanagi-Harada Syndrome Meningitis Behçet Syndrome Meningitis Neoplastic Meningitis IgG4-Related Hypertrophic Pachymeningitis Empirical Therapy for Presumed Tuberculous Meningitis Key References References 89 Encephalitis Short View Summary Clinical Syndromes Autoimmune Encephalitis General Clinical Approach Clinical Manifestations Diagnostic Tests Neuroimaging Cerebrospinal Fluid Analysis Cerebrospinal Fluid Profile Polymerase Chain Reaction and Antibody Studies Future diagnostic approaches. Electroencephalography Other Diagnostic Studies Management Viral Etiology of Encephalitis Herpesviruses Herpes Simplex Virus Types 1 and 2 Herpes Simplex Virus Pathogenesis Herpes Simplex Virus Encephalitis: Clinical Presentation Herpes Simplex Virus Encephalitis: Diagnosis Herpes Simplex Virus Encephalitis: Treatment and Outcomes HSV-2 Central Nervous System Disease Herpes Simplex Virus Myelitis Varicella-Zoster Virus Varicella-Zoster Virus Pathogenesis and Central Nervous System Disease Varicella-Zoster Virus Vasculopathy Varicella-Zoster Virus Meningitis Varicella-Zoster Virus Central Nervous System Disease Treatment Cytomegalovirus Epstein-Barr Virus Human Herpesvirus 6 Herpesvirus B Vector-Borne Viral Infections Encephalitic Arbovirus Pathogenesis West Nile Virus (Also See Chapter 153) West Nile Virus Pathogenesis West Nile Virus: Infection Clinical Features West Nile Virus Infection: Diagnosis West Nile Virus: Prevention and Treatment West Nile Virus: Infection Outcome St. Louis Encephalitis St. Louis Encephalitis Virus Infection: Clinical Features St. Louis Encephalitis Virus Infection: Diagnosis Zika Virus (Also See Chapter 153) Zika Virus Clinical Features Zika Virus: Transmission Zika Virus Infection: Diagnosis and Management Eastern Equine Encephalitis Virus Western Equine Encephalitis Venezuelan Equine Encephalitis Chikungunya California Encephalitis Group Japanese Encephalitis Influenza Colorado Tick Fever Virus (See Chapter 149) Enteroviruses Poliovirus Nonpoliovirus Enteroviruses Rabies Virus Measles Virus Key References References 90 Brain Abscess Short View Summary Epidemiology and Etiology Bacterial Brain Abscess Fungal Brain Abscess Protozoal and Helminthic Brain Abscess Pathogenesis and Pathophysiology Pathogenesis Natural History of Infection Clinical Presentation Diagnosis Initial Management of the Patient With Brain Abscess Therapy Bacterial Brain Abscess Antimicrobial Therapy Surgical Therapy Fungal Brain Abscess Key References References 91 Subdural Empyema, Epidural Abscess, and Suppurative Intracranial Thrombophlebitis Short View Summary Subdural Empyema Epidemiology and Etiology Clinical Features Diagnosis Management and Outcome Epidural Abscess Epidemiology and Etiology Clinical Features Diagnosis Management and Outcome Suppurative Intracranial Thrombophlebitis Epidemiology and Etiology Clinical Features Diagnosis Management and Outcome Key References References 92 Cerebrospinal Fluid Shunt and Drain Infections Short View Summary Epidemiology Etiology Pathogenesis Clinical Features Diagnosis Therapy Antimicrobial Therapy Intraventricular and Intrathecal Antimicrobial Therapy Shunt Removal Duration of Antimicrobial Therapy and Shunt Reimplantation Surgical Management of Ventriculoperitoneal Shunt–Related Peritoneal Pseudocyst Surgical Management of Intraventricular Empyema Prevention Antimicrobial Prophylaxis Antimicrobial-Impregnated Catheters Combined Interventions Key References References I Skin and Soft Tissue Infections 93 Cellulitis, Necrotizing Fasciitis, and Subcutaneous Tissue Infections Short View Summary Cellulitis and Superficial Infections Primary Pyodermas Impetigo Pathologic Characteristics and Pathogenesis Clinical Manifestations Laboratory Findings Etiologic Agents Differential Diagnosis Presumptive Therapy Bullous Impetigo Clinical Manifestations Presumptive Therapy Staphylococcal Scalded Skin Syndrome Clinical Manifestations Presumptive Therapy Staphylococcal Scarlet Fever Toxic Shock Syndrome Folliculitis Furuncles and Carbuncles Definition and Pathologic Characteristics Clinical Manifestations Presumptive Therapy Ecthyma Chancriform Lesions: Anthrax Pathogenesis Clinical Manifestations Presumptive Therapy Erysipelas Clinical Manifestations Differential Diagnosis Presumptive Therapy Cellulitis Clinical Manifestations Presumptive Therapy Membranous Ulcers Cutaneous Diphtheria Clinical Manifestations Laboratory Findings Differential Diagnosis Presumptive Therapy Infectious Gangrene (Gangrenous Cellulitis) Pathologic Characteristics and Pathogenesis Clinical Manifestations Streptococcal gangrene. Progressive bacterial synergistic gangrene. Gas gangrene, anaerobic cellulitis, and other forms of crepitant cellulitis. Gangrenous cellulitis in immunocompromised hosts. Differential Diagnosis Presumptive Therapy Erythrasma Secondary Bacterial Infections Complicating Preexisting Skin Lesions Diabetic Foot and Other Chronic Superficial Skin Ulcers Decubitus Ulcers Diabetic Ulcers Occupation-Related Ulcers Posttraumatic Opportunistic Skin Infections in Immunocompromised Patients Bacillary Angiomatosis in Patients With Acquired Immunodeficiency Syndrome Hidradenitis Suppurativa Infected Epidermal Cysts Self-Induced Skin Infections Cutaneous Involvement in Systemic Bacterial and Mycotic Infections Bacteremias Staphylococcus aureus Pseudomonas aeruginosa Neisseria meningitidis Neisseria gonorrhoeae Salmonella enterica Serovar Typhi Haemophilus influenzae Helicobacter cinaedi Infective Endocarditis Fungemias: Candida albicans and Other Yeasts Subcutaneous Tissue Infections and Abscesses Clostridial Anaerobic Cellulitis Pathologic Characteristics and Pathogenesis Clinical Manifestations Etiologic Agents Differential Diagnosis Presumptive Therapy Nonclostridial Anaerobic Cellulitis Necrotizing Fasciitis Clinical Manifestations Fournier gangrene. Other special anatomic forms of necrotizing fasciitis. Other microbial causes of necrotizing fasciitis. Differential Diagnosis Presumptive Therapy Synergistic Necrotizing Cellulitis Clinical Manifestations Etiologic Agents Presumptive Therapy Miscellaneous Infections Secondary to Trauma Bite Infections Burn Infections Injection Site Abscesses Factitial Disease (Self-Induced Abscesses) Subcutaneous Infections Originating in Contiguous Foci Osteomyelitis Actinomycosis Primary Pyodermas Subcutaneous Abscesses in the Course of Bacteremic Infections Mycetoma Key References References 94 Myositis and Myonecrosis Short View Summary Pyomyositis Pathogenesis and Pathologic Characteristics Clinical Manifestations Etiologic Agents Differential Diagnosis Diagnosis Empirical Therapy Group a Streptococcal Necrotizing Myositis Gas Gangrene (Clostridial Myonecrosis) Pathogenesis and Pathologic Characteristics Clinical Manifestations Laboratory Findings Etiologic Agents Differential Diagnosis Empirical Therapy Nonclostridial (Crepitant) Myositis Anaerobic Streptococcal Myonecrosis Synergistic Nonclostridial Anaerobic Myonecrosis Infected Vascular Gangrene Aeromonas hydrophila Myonecrosis Psoas Abscess Other Specific Sites of Muscle Abscesses Myalgias Influenza Infective Endocarditis Toxoplasmosis Other Causes Pleurodynia Syndromes Myalgias With Eosinophilia (Parasitic Myositis) Trichinosis Cysticercosis (Cysticercus cellulosae Myositis) Muscle Degeneration Associated With Infections at Other Sites Acute Rhabdomyolysis Muscle Proteolysis and Mediators of Fever in Patients With Sepsis Key References References 95 Lymphadenitis and Lymphangitis Short View Summary Lymphadenitis Pathogenesis and Pathologic Changes Acute Lymphadenitis Chronic Lymphadenitis Clinical Manifestations Acute Regional Lymphadenitis Due to Pyogenic Bacteria Syndromes Due to Suppurative Lymphadenitis at Specific Anatomic Sites Cervical Lymphadenitis Acute Axillary Lymphadenitis Subpectoral Lymphadenitis Deep Neck Space Lymphadenitis Acute Mediastinal Lymphadenitis Acute Suppurative Epitrochlear Lymphadenitis Suppurative Iliac Lymphadenitis Acute Regional Lymphadenitis Due to Infecting Agents Other Than Pyogenic Bacteria Specific Types of Nonpyogenic Regional Lymphadenitis Scrofula (Tuberculous Cervical Lymphadenitis) Granulomatous Lymphadenitis Caused by Nondiphtheria Corynebacteria Oculoglandular (Parinaud) Syndrome Cat-Scratch Disease Mediastinal Lymphadenopathy Inguinal Buboes of Sexually Transmitted Disease Inguinal Buboes of Other Than Sexually Transmitted Disease Origin Generalized Lymphadenitis Associated With Systemic Infections Recurrent Lymphadenitis Periodic Fever, Aphthous Ulcers, Pharyngitis, and Adenitis Syndrome Filarial Lymphangitis Etiologic Agents and Differential Diagnosis Generalized Lymphadenopathy With Acquired Immunodeficiency Syndrome Presumptive Treatment of Lymphadenitis Lymphangitis Pathologic Changes and Pathogenesis Clinical Findings Acute Lymphangitis Chronic Granulomatous Lymphangitis Pseudolymphangitis Etiologic Agents Differential Diagnosis Presumptive Therapy Key References References J Gastrointestinal Infections and Food Poisoning 96 Syndromes of Enteric Infection Short View Summary Occurrence and Scope of Gastrointestinal Infections Occurrence and Scope of Gastrointestinal Infections in High-Income Countries Pathogens Associated With Gastrointestinal Infections Environmental Risk Factors for Gastrointestinal Infection Host Factors in Gastrointestinal Infection Age Gastric Acidity and Physical Barriers Intestinal Microbiome Immunocompromise Genetic Determinants Nutritional Status Microbial Factors in Gastrointestinal Infection Inoculum Size Adherence/Attachment Invasion Toxins Neurotoxins Enterotoxins Cytotoxins Major Clinical Syndromes Acute Vomiting Acute Watery Diarrhea Diarrhea With Fever Persistent Diarrhea Enteric Fever Complications of Acute Enteric Infection Asymptomatic Passage of Enteropathogens Diagnostic Approach to Enteric Infections Therapy for Enteric Infections Prevention and Control of Enteric Infections Key References References 97 Esophagitis Short View Summary Clinical Manifestations Specific Etiologic Agents Candida Esophagitis Diagnosis Radiology Cytomegalovirus Esophagitis Herpes Simplex Virus Esophagitis Diagnosis Aphthous (Idiopathic) Ulceration of the Esophagus Management of Esophageal Infection General Considerations in Therapy Esophagitis in Patients With Acquired Immunodeficiency Syndrome Key References References 98 Diarrhea With Little or No Fever Short View Summary Epidemiology of Acute Noninflammatory Diarrhea Community-Acquired Diarrhea Acute Pediatric Diarrhea Diarrhea Caused by Rotavirus Acute Nausea and Vomiting (Winter Vomiting Disease) Norovirus Sapovirus Diarrhea Caused by Astrovirus, Adenovirus, and Other Possible Viral Etiologies Cryptosporidiosis Diarrhea Due to Enteropathogenic Bacteria Diarrhea in Adults Diarrhea in Immunocompromised Patients Patients With HIV Infection Patients With Solid-Organ Transplants and Others Receiving Immunosuppressants Travel-Associated Diarrhea (Turista) Diarrhea in Institutions Epidemic Nosocomial Diarrhea in Newborns Hospitals Long-Term Care Facilities Daycare Centers Treatment of Acute Noninflammatory Diarrhea Chronic Noninflammatory Diarrhea Bacterial Overgrowth Syndromes Brainerd Diarrhea Other Noninfectious Mimics of Gastroenteritis Acknowledgment Key References References 99 Acute Dysentery Syndromes (Diarrhea With Fever) Short View Summary Definition Epidemiology Microbiology and Pathogenesis of the Major Causes of Acute Dysenteric Syndromes Shigella spp. and Enteroinvasive Escherichia coli Shiga Toxin–Producing Escherichia coli Enteropathogenic and Enteroaggregative Escherichia coli Campylobacter Enteritis Clostridioides difficile Colitis Vibriosis Salmonellosis and Enteric Fever Yersiniosis Amebiasis Diagnosis Therapy Prevention Other Acute Infectious/Inflammatory Processes Involving the Intestinal Tract Gonococcal Proctitis Unusual Causes of Dysentery Necrotizing Enterocolitis in the Newborn Darmbrand, Pig-Bel, Necrotizing Enteritis in Adults (Enteritis Necroticans) Chronic Infectious/Inflammatory Processes Involving the Intestinal Tract Syphilis Gastrointestinal Tuberculosis Key References References 100 Typhoid Fever, Paratyphoid Fever, and Typhoidal Fevers Short View Summary Enteric Fever (Typhoid and Paratyphoid Fever) History Etiologic Agents of Enteric Fever Nomenclature and Classification of Typhoidal Salmonella enterica Clinical Distinction Between Typhoidal and Nontyphoidal Salmonella enterica Genomic Features Epidemiology Burden and Distribution Severity Source of Infection Mode of Transmission Acquisition of Disease in Areas Where Enteric Fever Occurs Sporadically Antibiotic Resistance and Emergence of Pandemic Salmonella Typhi Host Factors and Susceptibility to Infection Pathogenesis Invasion Latency and Dissemination Intestinal and Other Local Pathology Relapse and Chronic Carriage Clinical Manifestations Uncomplicated Typhoid Fever Laboratory Findings in Uncomplicated Infection Severe Illness Gastrointestinal Complications Neurologic Complications Metastatic Pyogenic Complication Diagnosis Culture-Based Diagnostics Serologic Tests Molecular Approaches Screening for Chronic Carriage Management Chloramphenicol, Ampicillin, and Trimethoprim-Sulfamethoxazole Fluoroquinolones Cephalosporins Azithromycin Other Antibiotics Adjunctive Therapy Supportive Care and Management of Complications Treatment of Relapse and Chronic Carriage Prevention Differential Diagnosis of Enteric and Typhoidal Fevers Bacteremia Associated With Nontyphoidal Salmonella Typhoidal Fever Additional Causes of Prolonged or Persistent Fever Assessing an Individual With an Acute Febrile Illness in a Resource-Limited Area or After International Travel Fever and Mesenteric Adenitis or Ileocecitis Fever, Abdominal Pain, and Peripheral Eosinophilia Key References References 101 Foodborne Disease Short View Summary Clinical Manifestations and Pathogenesis Foodborne Syndromes Caused by Microbial Agents or Their Toxins Nausea and Vomiting Lasting Less Than 24 Hours Watery Diarrhea Without Fever Lasting 1 to 2 Days Watery Diarrhea and Abdominal Cramps Lasting More Than 2 Days Diarrhea, Abdominal Cramps, and Fever Bloody Diarrhea With Minimal Fever Persistent Diarrhea Lasting 2 or More Weeks Cranial Nerve Palsies and Descending Paralysis Systemic Illness Postinfection Syndromes Foodborne Syndromes Caused by Nonbacterial Toxins Nausea, Vomiting, and Abdominal Cramps Associated With Heavy Metal Ingestion Histamine Reaction After Eating Seafood Paresthesias After Eating Shellfish Gastrointestinal, Neurologic, and Cardiovascular Symptoms After Eating Fish Rapid Paralysis After Eating Puffer Fish Diarrhea and Chills Within 12 Hours After Eating Shellfish Diarrhea, Abdominal Cramps, Memory Loss, and Disorientation After Eating Shellfish Abdominal Cramps, Vomiting, and Diarrhea Followed by Hepatorenal Failure Miscellaneous Other Mushroom Poisoning Syndromes With Onset Within 2 Hours Epidemiology Foods Nonfoodborne Transmission Vulnerable Populations Seasonality Geographic Location Epidemiologic Assessment Laboratory Diagnosis Diagnosis in Foodborne Outbreaks Specific Considerations About Important Pathogens Staphylococcus aureus Bacillus cereus Clostridium perfringens Classic Bacterial Enteropathogens Botulism Protozoa Heavy Metals Unknown or Rare Causes Therapy Surveillance Prevention Key References References 102 Tropical Sprue and Environmental Enteric Dysfunction Short View Summary Tropical Sprue Environmental Enteric Dysfunction Exposures/Epidemiology Tropical Sprue Environmental Enteric Dysfunction Clinical Features Tropical Sprue Environmental Enteric Dysfunction Pathogenesis Tropical Sprue Intestinal Abnormalities Tropical Sprue Histopathology Tropical Sprue Environmental Enteric Dysfunction Diagnosis Tropical Sprue Environmental Enteric Dysfunction Increased Intestinal Permeability/Impaired Gut Barrier Integrity Intestinal Damage and Repair Mucosal and Systemic Inflammation Microbial Translocation and Immune Activation Fecal Messenger mRNA Transcripts Therapy Tropical Sprue Environmental Enteric Dysfunction Key References References K Bone and Joint Infections 103 Infectious Arthritis of Native Joints Short View Summary Acute Bacterial Arthritis Epidemiology Route of Infection Predisposing Host Factors Nongonococcal Arthritis Pathophysiology Microbiology Gram-Positive Bacteria Gram-Negative Bacteria Other Bacteria Clinical Manifestations Joints Involved Clinical Presentation Laboratory Findings Microbiologic Diagnosis Conventional culture. Molecular tests. Radiographic Features Gonococcal Arthritis Epidemiology Pathogenesis Antimicrobial Resistance Clinical Manifestations Laboratory Testing Septic Arthritis in Persons Who Inject Drugs Management Initial Approach to the Patient Patient Assessment Laboratory Assessment Synovial Fluid Assessment Other Analysis Differential Diagnosis Crystalline Arthritis Other Causes of Arthritis Therapy Joint Drainage Antimicrobial Therapy Initial antimicrobial selection. Antimicrobial deescalation. Directed therapy for MRSA infections. Directed therapy for other situations. Duration of therapy. Adjuvant Therapy Viral Arthritis Parvovirus B19 Alphaviruses, Including Chikungunya Other Causes of Viral Arthritis Chronic Infectious Arthritis Fungal Arthritis Candida Arthritis Cryptococcus Arthritis Arthritis Due to Dimorphic Fungi Arthritis Due to Molds Therapy for Fungal Arthritis Mycobacterial Arthritis Tuberculosis Arthritis Clinical Features Diagnosis Treatment Nontuberculous Mycobacterial Arthritis Septic Bursitis Key References References 104 Osteomyelitis Short View Summary Classification Lessons From Experimental Models Pathogenesis in Experimental Models Antimicrobial Therapy in Experimental Models General Principles General Principles of Diagnosis General Principles of Microbiologic Diagnosis General Principles of Therapy Established Agents for Antimicrobial Therapy Oral Agents for Antimicrobial Therapy New Agents for Antimicrobial Therapy Duration of Antimicrobial Therapy Hyperbaric Oxygen Therapy Osteomyelitis After a Contaminated Open Fracture Microbiology of Osteomyelitis After Contaminated Open Fracture Management of Open Contaminated Fractures to Prevent Osteomyelitis Signs and Symptoms of Osteomyelitis After Contaminated Open Fracture Management of Osteomyelitis After Contaminated Open Fracture Vertebral Osteomyelitis and Spondylodiskitis Clinical Signs and Symptoms of Vertebral Osteomyelitis Microbiology of Vertebral Osteomyelitis Diagnosis of Vertebral Osteomyelitis Microbiologic Diagnosis of Vertebral Osteomyelitis Therapy for Vertebral Osteomyelitis Role of Surgery for Vertebral Osteomyelitis Follow-Up Evaluation for Vertebral Osteomyelitis Hardware-Associated Vertebral Infection Osteomyelitis in Patients With Diabetes Mellitus or Vascular Insufficiency Prevention of Diabetic Foot Osteomyelitis Diagnosis of Osteomyelitis in Patients With Diabetes or Vascular Insufficiency Management of Osteomyelitis in Patients With Diabetes or Vascular Insufficiency Antimicrobial Therapy for Osteomyelitis in Patients With Diabetes or Vascular Insufficiency Acute Hematogenous Osteomyelitis Pathophysiology of Acute Hematogenous Osteomyelitis Microbiology of Acute Hematogenous Osteomyelitis Management of Acute Hematogenous Osteomyelitis SAPHO Syndrome Diagnosis of SAPHO Syndrome Management of SAPHO Syndrome Other Forms of Osteomyelitis: Specific Hosts, Unusual Locations, or Unusual Organisms Osteitis Pubis Sterile Osteitis Pubis Osteomyelitis of the Clavicle Osteomyelitis in Hemodialysis Patients Osteomyelitis in Patients With Sickle Cell Disease Gaucher Disease Osteomyelitis in Injection Drug Users Skeletal Mycobacterial Infection Vertebral Tuberculosis (Pott disease) Diagnosis of Tuberculous Osteomyelitis Nontuberculous Mycobacterial Osteomyelitis Fungal Osteomyelitis Brodie Abscess Culture-Negative Osteomyelitis Summary Key References References 105 Orthopedic Implant– Associated Infections Short View Summary Periprosthetic Joint Infection Definition Pathogenesis Classification Risk Factors Patient Characteristics Surgery-Related Risk Factors Postoperative Factors Risk During Bacteremia Microbiology Clinical Manifestations and Differential Diagnosis Acute Periprosthetic Joint Infection Chronic Periprosthetic Joint Infection Diagnostic Procedures Blood Tests Synovial Fluid Cell Counts Synovial Fluid Culture Intraoperative Samples for Culture and Histopathology Sonication Novel Diagnostic Procedures α-Defensin Test Molecular Diagnostics Imaging Procedures Positron Emission Tomography Treatment Concepts General Aspects Débridement With Retention of Implant One-Stage Exchange Two-Stage Exchange Antimicrobial Therapy Internal Fixation– Associated Infection Definition Incidence of Infection Pathogenesis and Classification Microbiology Clinical Manifestations Diagnostic Procedures Microbiology and Histopathology Imaging Treatment Concepts General Aspects Systemic Antimicrobial Therapy Local Antimicrobial Therapy Surgical Interventions Plate-Associated Osteomyelitis Intramedullary Nail–Associated Osteomyelitis Pin-Tract Infection Prevention in Orthopedic Surgery Perioperative Antimicrobial Prophylaxis Arthroplasty and Closed Fractures Open Fractures Prevention of Hematogenous Infection Key References References L Diseases of the Reproductive Organs and Sexually Transmitted Diseases 106 Genital Skin and Mucous Membrane Lesions Short View Summary History of Presentation Clinical Manifestations Location Pain, Dysesthesias, and Systemic Symptoms Lymphadenopathy Lesion Morphology Duration Epidemiology Genital Lesions in Patients With Human Immunodeficiency Virus Laboratory Testing Therapy Other Management Issues Nonvenereal Genital Lesions Key References References 107 Urethritis Short View Summary Examination of the Urethra Examination of the Urethral Specimen and Consideration of Etiologies Noninfectious Urethritis Infectious Urethritis Gonococcal and Nongonococcal Urethritis Etiology of Nongonococcal Urethritis Postgonococcal Urethritis Persistent or Recurrent Urethritis Asymptomatic Urethral Infection Urethral Syndrome and Related Diseases of Women Complications of Urethritis Therapy Therapy for Sexual Partners of Men With Nongonococcal Urethritis Reactive Arthritis Clinical Manifestations Laboratory Findings Therapy Key References References 108 Vulvovaginitis and Cervicitis Short View Summary Vaginal Secretions Approach to the Patient History Age Mode of Onset Quantity of Discharge External Irritation Odor Abdominal Pain Sexual History Other Diseases Medications Physical Examination Diagnostic Evaluation Trichomoniasis Epidemiology Etiology and Pathogenesis Diagnosis Therapy Pregnancy Vulvovaginal Candidiasis Etiology and Pathogenesis Clinical Manifestations Diagnosis Therapy Bacterial Vaginosis Epidemiology Pathophysiology Dysbiosis Hydrogen Peroxide Production Biofilm Formation Risk Factors Diagnosis Therapy Pregnancy Desquamative Inflammatory Vaginitis Etiology and Pathogenesis Diagnosis Therapy Cervicitis Etiology and Pathogenesis Symptoms and Diagnosis Therapy Estrogen-Deficiency Vaginitis (Genitourinary Syndrome) Etiology and Pathogenesis Diagnosis Therapy Vulvar Pain Syndrome (Formerly Vulvodynia, Vestibulodynia, Vulvar Vestibulitis, or Focal Vulvitis) Definition and Terminology Epidemiology Etiology and Pathogenesis Clinical Manifestations Diagnosis Therapy Key References References 109 Infections of the Female Pelvis Short View Summary Intrapartum, Postpartum, and Postabortal Infections Postpartum Endometritis Refractory Postpartum Fever of Undetermined Origin Infections After Perineal Lacerations Postabortal Infections Surgical Site Infection After Gynecologic Surgery Pathogenesis Risk Factors Cuff Cellulitis Pelvic Abscess Osteomyelitis Pubis Pelvic Inflammatory Disease Risk Factors Diagnosis Management of Acute Pelvic Inflammatory Disease Management of Suspected Tubo-ovarian Abscess Sequelae Acknowledgment Key References References 110 Prostatitis, Epididymitis, and Orchitis Short View Summary Anatomy and Physiology of the Testes and Male Accessory Sex Organs Host Defenses of the Male Lower Urogenital Tract Prostatitis Classification Acute Bacterial Prostatitis Chronic Bacterial Prostatitis Chronic Prostatitis/Chronic Pelvic Pain Syndrome Asymptomatic Inflammatory Prostatitis Granulomatous Prostatitis Prostatic Abscess Epididymitis Nonspecific Bacterial Epididymitis Sexually Transmitted Epididymitis Follow-Up Orchitis Viral Orchitis Bacterial Orchitis Urologic Manifestations in Men With HIV Infection Semen as a Vector for HIV Infection Semen as a Vector for Zika Virus Infection Key References References M Eye Infections 111 Introduction to Eye Infections Anatomy Types of Eye Infections Conjunctivitis Keratitis Endophthalmitis Uveitis Periocular Infections Understanding the Ophthalmologist’s Note Visual Acuity and Measuring Low Vision Intraocular Pressure Ophthalmology Examination Case Example 1 Ophthalmologist’s Examination Discussion Case Example 2 Ophthalmologist’s Examination Discussion Ophthalmic Glossary of Interest to the Infectious Diseases Practitioner Conclusion 112 Microbial Conjunctivitis Short View Summary Conjunctivitis Anatomy and Physiology Clinical Presentation History and Physical Examination Eye Pain Itching Visual Acuity Conjunctival Hyperemia Periocular and Periorbital Skin Discharge Conjunctival Edema (Chemosis) and Conjunctivochalasis Conjunctival Papillae Conjunctival Follicles Membranes and Pseudomembranes Conjunctival Phlyctenules and Granulomas Corneal Involvement Preauricular Adenopathy Laboratory Evaluation Viral Conjunctivitis Adenoviral Conjunctivitis Pharyngoconjunctival Fever Epidemic Keratoconjunctivitis Acute Hemorrhagic Conjunctivitis Herpes Simplex Conjunctivitis Varicella and Varicella-Zoster Conjunctivitis Variola (Smallpox) Conjunctivitis Vaccinia Conjunctivitis Other Viral Etiologies Chlamydial Conjunctivitis Chlamydia trachomatis Infection Chlamydia pneumoniae Infection Trachoma Adult Inclusion Conjunctivitis Treatment of Adult Inclusion Conjunctivitis Lymphogranuloma Venereum Bacterial Conjunctivitis Pathogenesis Acute (Mucopurulent) Bacterial Conjunctivitis Treatment of Acute Bacterial Conjunctivitis Hyperacute (Purulent) Bacterial Conjunctivitis Treatment of Hyperacute Bacterial Conjunctivitis Chronic Bacterial Conjunctivitis Treatment of Chronic Bacterial Conjunctivitis Neonatal Conjunctivitis Neonatal Chemical Conjunctivitis Neonatal Chlamydial Conjunctivitis Neonatal Gonococcal Conjunctivitis Nongonococcal Neonatal Bacterial Conjunctivitis Neonatal Viral (Herpetic) Conjunctivitis Parinaud Oculoglandular Conjunctivitis Parasitic Conjunctivitis Leishmaniasis Other Parasites and Ectoparasites Fungal Conjunctivitis Noninfectious Vision-Threatening Conditions Associated With Red Eye Key References References 113 Microbial Keratitis Short View Summary Etiologic Agents and Risk Factors Microbial Agents Anatomic Protection Geographic Variation Risk Factors Contact Lenses Laboratory Data and Clinical Response Clinical Presentation Eye Pain Conjunctival Injection and Discharge Corneal Infiltrates Epithelial Defect Stromal Suppuration Corneal Edema Corneal Neovascularization Intraocular Inflammatory Reaction Stromal Melting (Keratolysis) Laboratory Evaluation Stains and Media Inoculation Viral Cultures Bacterial Keratitis Etiology Pathogenesis Geographic Variation Gram-Positive Bacteria Gram-Negative Bacteria Mycobacteria Therapy for Bacterial Keratitis Immediate, Aggressive Therapy Hospital Admission Antibiotic Solutions Local and Systemic Administration Contact Lenses and Collagen Shields Unique Pharmacokinetics With Topical Antibiotics Initial Therapy Topical Fluoroquinolones Comparison of Fluoroquinolones and Fortified Antibiotics Proposed Therapy Guidelines Topical Corticosteroids Supportive Measures Chlamydial and Syphilitic Keratitis Chlamydial Keratitis Ocular Associations With Chlamydia Syphilitic Keratitis (Interstitial Keratitis) Therapy for Chlamydial and Syphilitic Keratitis Therapy for Interstitial Keratitis (Syphilitic and Lyme Associated) Viral Keratitis Herpes Simplex Virus Primary Herpes Simplex Virus Keratitis Recurrent Keratitis Stromal Inflammation and Intraocular Reaction Neurotrophic Keratitis Varicella-Zoster Virus Herpes Zoster Ophthalmicus Clinical Manifestations of Herpes Zoster Ophthalmicus Corneal Anesthesia Ocular Complications With Vaccinia (Smallpox) Vaccination Vaccinia Keratitis Adenoviral Keratitis Differential Diagnosis of Epidemic Keratoconjunctivitis Therapy for Viral Keratitis Self-Limited Cases Therapy for Herpes Simplex Virus and Varicella-Zoster Virus Therapy for Ocular Vaccinia Therapy for Viral Keratoconjunctivitis Fungal Keratitis Clinical Presentation Fusarium Keratitis Candida Keratitis Therapy for Fungal Keratitis: Limited Therapy Options Parasitic Keratitis Acanthamoeba Keratitis Clinical Signs and Symptoms With Acanthamoeba Keratitis Onchocerciasis Leishmaniasis Microsporidia and Trypanosomes Therapy for Parasitic Keratitis Novel Therapeutics Key References References 114 Endophthalmitis Short View Summary Categories Acute Postoperative Endophthalmitis Chronic Postcataract Endophthalmitis Postinjection Endophthalmitis Bleb-Related Endophthalmitis Posttraumatic Endophthalmitis Keratitis-Related Endophthalmitis Endogenous Bacterial Endophthalmitis Mycobacterial Endophthalmitis Fungal Endophthalmitis Endogenous Candida Endophthalmitis Exogenous Candida Endophthalmitis Mold Endophthalmitis Diagnosis Therapy Acute Bacterial Endophthalmitis Chronic Postcataract Endophthalmitis Fungal Endophthalmitis Endogenous Candida Endophthalmitis Exogenous Candida Endophthalmitis Mold Endophthalmitis Visual Outcome Preventing Endophthalmitis Prophylaxis for Eye Surgery Prophylaxis for Intravitreal Injections Prophylaxis for Eye Trauma Key References References 115 Infectious Causes of Uveitis Short View Summary Epidemiology Clinical Manifestations Acute Retinal Necrosis Brucellosis Cat-Scratch Disease Chikungungya Virus Cytomegalovirus Anterior Uveitis Cytomegalovirus Retinitis Dengue Ebola Virus Herpetic Anterior Uveitis Leprosy Leptospirosis Lyme Disease Presumed Ocular Histoplasmosis Syndrome Progressive Outer Retinal Necrosis Syphilis Ocular Toxocariasis Toxoplasmosis Tuberculosis West Nile Virus Whipple Disease Zika Virus Endophthalmitis Mimicking Uveitis Chronic Postcataract Endophthalmitis Chronic Endophthalmitis Due to Fungi Diagnosis of Infectious Uveitis Approach to the Patient With Uveitis Therapy Key References References 116 Periocular Infections Short View Summary Eyelid Infections Anatomy Hordeolum Chalazion Blepharitis Infections of the Lacrimal System Anatomy Dacryoadenitis Canaliculitis Dacryocystitis Preseptal Cellulitis and Orbital Infections Anatomy Epidemiology Etiology and Bacteriology Clinical Manifestations Preseptal and Orbital Cellulitis Orbital and Subperiosteal Abscesses Orbital Apex, Superior Orbital Fissure, and Cavernous Sinus Syndromes Cavernous Sinus Thrombophlebitis Laboratory and Radiologic Studies Therapy Key References References N Hepatitis 117 Viral Hepatitis Short View Summary Acute Viral Hepatitis Clinical Manifestations Laboratory Features Prognosis of Acute Hepatitis Fulminant Hepatitis Complications of Acute Hepatitis Agents of Viral Hepatitis Hepatitis A Virus (Also See Chapter 174) Hepatitis B Virus (Also See Chapter 145) Hepatitis C Virus (Also See Chapter 154) Hepatitis D Virus (Also See Chapter 146) Hepatitis E Virus (Also See Chapter 178) Diagnosis Differential Diagnosis Treatment Prevention Hepatitis A Hepatitis B Hepatitis C Hepatitis D Hepatitis E Chronic Viral Hepatitis Chronic Hepatitis B Distinctions Based on Relative Levels of Hepatitis B Virus Replication Distinctions Based on Epidemiologic Considerations Distinctions Based on Viral Variants Pathophysiology and Natural History Clinical Manifestations Treatment Interferon-Based Therapy for Chronic Hepatitis B Direct Oral Antiviral Agents Lamivudine. Adefovir dipivoxil. Entecavir. Telbivudine. Tenofovir. Other Agents for Chronic Hepatitis B Optimal Use of Available Agents for Hepatitis B Recommendations for Therapy Choice of Antiviral Agents Special Patient Populations Pregnancy Liver Transplantation HIV Coinfection (Also See Chapter 124) Immune-Complex Disease Oncology Patients Who Need Cytotoxic Chemotherapy Chronic Hepatitis D Treatment Chronic Hepatitis C Pathophysiology and Natural History Clinical Manifestations Hepatitis C Virus–HIV Coinfection (Also See Chapter 124) Treatment Pegylated Interferon and Ribavirin: Standard of Care 2001 to 2011— Treatment Principles Established Tailored pegylated interferon and ribavirin therapy. Clinical benefits of interferon-based therapy. First-Generation NS3-4A Protease Inhibitors for Chronic Hepatitis C: Boceprevir and Telaprevir—Standard of Care for Genotype 1, 2011–13 Second-Generation NS3-4A Protease Inhibitor and First-Generation Nucleoside Polymerase Inhibitor for Chronic Hepatitis C: Simeprevir and Sofosbuvir—Standard of Care, 2014–15 First-Generation NS5A Inhibitors, Second-Generation Nucleoside Polymerase Inhibitors, and Third-Generation NS3-4A Protease Inhibitors—Standard of Care, 2015 to September 2017 Ledipasvir-sofosbuvir (Harvoni). Ritonavir-booster paritaprevir, ombitasvir, and dasabuvir (Viekira Pak). Elbasvir-Grazoprevir (Zepatier). Daclatasvir (Daklinza). Paritaprevir-ritonavir-ombitasvir (Technivie). Second-Generation NS5A Inhibitors and Fourth-Generation NS3-4A Protease Inhibitors—Standard of Care, September 2017 Sofosbuvir-velpatasvir (Epclusa). Sofosbuvir-velpatasvir-voxilaprevir (Vosevi). Glecaprevir-pibrentasvir (Mavyret). Considerations in Direct-Acting Antiviral Therapy of Chronic Hepatitis C The role of resistance testing. Reactivation of hepatitis B. Does DAA cure increase the risk of HCC? Candidates for Therapy Challenge to Benefits of Direct-Acting Antiviral Therapy Special Patient Populations Liver Transplantation HIV Coinfection (Also See Chapter 124) Immune-Complex Disease B-Cell Lymphoma Other Special Populations Chronic Hepatitis E Treatment Key References References O Acquired Immunodeficiency Syndrome 118 Global Perspectives on Human Immunodeficiency Virus Infection and Acquired Immunodeficiency Syndrome Size of the Problem Western Europe Eastern Europe and Central Asia Sub-Saharan Africa Middle East and North Africa Asia and the Pacific Latin America and the Caribbean Dynamics of the Spread of Human Immunodeficiency Virus Modes of Transmission Reducing the Spread of Human Immunodeficiency Virus Safer Sexual Behavior Male Circumcision Preexposure Prophylaxis Treatment as Prevention Combination Prevention Demography and Social Context Gender Stigma and Discrimination Impact of Prevention and Care Programs Impact of the AIDS Epidemic Global Responses to AIDS Key References References 119 Epidemiology and Prevention of AIDS and HIV Infection, Including Preexposure Prophylaxis and HIV Vaccine Development HIV and AIDS Surveillance in the United States HIV Infection and AIDS in Adults Incidence and Prevalence of AIDS and HIV in the United States (Also See Chapter 118 for Global Data) Serologic Monitoring of the HIV Epidemic Exposure Categories AIDS Trends Demographic Characteristics of HIV Infection Geographic Distribution of HIV Infection Clinical Manifestations of HIV Infection Spectrum and Progression of HIV Infection AIDS-Indicator Diseases HIV Infection and Tuberculosis Mortality of Persons With HIV Infections and AIDS HIV/AIDS in Children Modes of Transmission Sexual Transmission Infectiousness of the Source Partner Susceptibility of the Recipient Partner Transmission Through Injection Drug Use Transmission by Blood and Other Tissues Perinatal Transmission Transmission of HIV in Health Care Settings Other Modes of Transmission HIV Infection and AIDS Outside the United States HIV-2 Prevention of HIV Infection Prevention of Sexual Transmission Preexposure Prophylaxis Prevention of Transmission by Injection Drug Use Prevention of Transmission Through Blood and Other Tissues Prevention of Transmission in the Health Care Setting Prevention of Perinatal Infection Counseling and HIV Antigen/Antibody Testing Vaccines for HIV Type 1 Infection Animal Models Human Trials Phase II Clinical Studies Phase IIb and III Efficacy Studies Broadly Neutralizing Antibodies Against HIV-1 Early Phase Clinical Trials Summary Key References References 120 Diagnosis of Human Immunodeficiency Virus Infection Short View Summary Background/Perspective Laboratory Advances Implementation of HIV Diagnostics Reporting HIV Infection Terminology and Performance Characteristics Specific Laboratory Methods for Detection of HIV Infection Immune Responses to HIV HIV Screening Assays Serologic Techniques to Detect Anti-HIV Antibody Standard ELISA Assays Particle Agglutination Assays Alternative ELISA Formats: Simple/Rapid Tests Saliva as Source of Patient Material for ELISA Assay Urine as Source of Patient Material for ELISA Serologic Techniques to Screen for HIV Antigens Fourth-Generation HIV Antigen-Antibody Assays False-Positive and False-Negative Results in Screening Tests for HIV Antibody Nonserologic Techniques to Screen for HIV Hybridization and Amplification Assays to Detect HIV Nucleic Acids HIV Supplemental and Confirmatory Assays HIV-1/2 ELISA for Confirmation of HIV Infection Western Blotting Immunofluorescence Virologic Techniques to Detect HIV Infection Diagnostic Algorithms and Practical Application of HIV Detection Assays HIV-1/2 Screening Phase Acute HIV Infection HIV-1/2 Supplemental Analysis Test Counseling Alternative Strategies for Screening/Confirmation HIV Detection Specific Circumstances and Special Populations HIV Diagnosis in Individuals Undergoing Preexposure Prophylaxis Detection of HIV-2 and HIV-1/2 Dual Infections Detecting Non-B HIV-1 Types and Subtypes Other Than Subtype B Detecting HIV-1 Dual Infections HIV Testing During Pregnancy or at Delivery HIV in Perinatal Diagnosis HIV Testing for Blood Donor Screening HIV Testing in Tissue Procurement for Transplantation HIV Testing in Vaccine, Prevention, Postexposure, and Gene Therapy Studies HIV Testing in Gene Therapy Studies Using Lentiviral Vectors HIV Infection but Viral RNA Less Than 50 Copies/mL: HIV Elite Controllers HIV Testing in the Setting of Acute Retroviral Syndrome or Other Acute Illness HIV Testing in Occupational Exposure HIV Testing in Idiopathic CD4 Lymphopenia Factitious HIV Infection and AIDS Phobia HIV Testing to Estimate Duration of Infection and Incidence Home Collection and Self-Testing for HIV Other Human Retroviral Infections and New Retroviral Zoonoses Regulatory Issues Regulation of HIV Testing Modalities Regulation of HIV Reporting Conclusion Acknowledgments Key References References 121 The Immunology of Human Immunodeficiency Virus Infection HIV Entry and Dissemination HIV Receptors and Entry Into Cells Dissemination of HIV Infection HIV-Specific Immune Responses Humoral Immune Responses Cellular Immune Responses Cytotoxic T Lymphocytes Soluble CD8+ T-Cell–Secreted Factors CD4+ T-Cell Responses Host Genetic Factors Long-Term Nonprogressors/Elite Controllers Host Immune Response Factors Virologic Factors Reservoirs of HIV Infection Latent Reservoirs of HIV Lymphoid Tissues Strategies for HIV Eradication Immune Dysfunction Caused by HIV Infection Lymphoid Tissues CD4+ T Cells Mechanisms of CD4+ T-Cell Depletion Increased Destruction Direct infection. Death by apoptosis and pyroptosis. Lymphocyte turnover. Decreased Production Redistribution. CD8+ T Cells B Cells Natural Killer Cells Monocytes and Macrophages Dendritic Cells Role of Immune Activation in the Pathogenesis of HIV Infection Cytokines and HIV Disease: Dysregulation of Cytokine Production Role of Cytokines as Therapeutic Agents in HIV Infection Conclusions Key References References 122 General Clinical Manifestations of Human Immunodeficiency Virus Infection (Including Acute Retroviral Syndrome and Oral, Cutaneous, Renal, Ocular, Metabolic, and Cardiac Diseases) Short View Summary History Natural History of HIV Infection Classification of HIV Infection Clinical Manifestations Effect of Antiretroviral Therapy on Natural History of HIV Infection Acute Retroviral Syndrome Persistent Generalized Lymphadenopathy Constitutional Disease and Wasting Metabolic and Endocrine Abnormalities Oral Disease Oral Candidiasis Oral Hairy Leukoplakia Gingivitis and Periodontitis Oral Ulcers Other Oral Lesions Musculoskeletal Complications Cutaneous Manifestations Viral Infections of the Skin and Mucous Membranes Bacillary Angiomatosis Kaposi Sarcoma Other Cutaneous Manifestations Scabies Renal Disease Ocular Complications Cardiac Manifestations Hematologic Manifestations Non–AIDS-Related Cancers Immune Reconstitution Syndromes Tuberculosis Mycobacterium avium Complex Disease Cytomegalovirus Disease Infection With Varicella-Zoster Virus Viral Hepatitis Other Diseases Key References References 123 Pulmonary Manifestations of Human Immunodeficiency Virus Infection Short View Summary Epidemiology Differential Diagnosis Clinical or Laboratory Stage of Immunosuppression Tempo of the Illness Receipt and Type of Pneumocystis Prophylaxis Receipt of Antiretroviral Therapy History of Opportunistic Processes Injection Drug Use and Smoking Local Epidemiology or Past Residence Characteristic Radiographic Findings Triage of Patients: Infection Control Issues Diagnostic Tests Specific Pathogens Pneumocystis Jirovecii Pneumonia Bacterial Pneumonia Mycobacterial Pneumonia Fungal Pneumonia Viral Pneumonia Parasitic Pneumonia Neoplastic and Other Noninfectious Pulmonary Complications of HIV Infection Treatment Key References References 124 Gastrointestinal, Hepatobiliary, and Pancreatic Manifestations of Human Immunodeficiency Virus Infection Short View Summary Disorders of the Esophagus Disorders of the Stomach Disorders of the Biliary Tree and Gallbladder Disorders of the Liver Disorders of the Pancreas Disorders of the Small and Large Intestine Key References References 125 Neurologic Diseases Caused by Human Immunodeficiency Virus Type 1 and Opportunistic Infections Short View Summary Principal Neurologic Manifestations of HIV Type 1 Infection Meningeal Syndrome Patient Otherwise Asymptomatic, CD4+ T-Lymphocyte Counts >200 Cells/µL: Aseptic Meningitis Clinical presentation. Laboratory investigations. Treatment. Patient at Any Stage of HIV-1 Infection and CD4+ T-Lymphocyte Counts at Any Level: Syphilitic Meningitis Clinical presentation. Laboratory investigations. Treatment. Patient With AIDS, CD4+ T-Lymphocyte Counts of <200 Cells/µL: Cryptococcal Meningitis Clinical presentation. Laboratory investigations. Treatment. Differential Diagnosis of Meningitis Cognitive and Motor Syndromes HIV Type 1–Associated Neurocognitive Disorder Clinical presentation. Laboratory investigations. Imaging studies. Brain biopsy and histologic analysis. Treatment. Central Nervous System Mass Lesions Toxoplasma Encephalitis Clinical presentation. Laboratory investigations. Imaging studies. Brain biopsy. Treatment. Secondary prophylaxis. Primary Central Nervous System Lymphoma Clinical presentation. Laboratory investigations. Imaging studies. Brain biopsy. Treatment. Progressive Multifocal Leukoencephalopathy Clinical presentation. Laboratory investigations. Imaging studies. Brain biopsy. Treatment. Inflammatory Progressive Multifocal Leukoencephalopathy Cytomegalovirus Encephalitis Clinical presentation. Laboratory investigations. Imaging studies. Brain biopsy. Treatment. Miscellaneous Mass Lesions and Rationale for Brain Biopsy Spinal Syndrome Vacuolar Myelopathy Clinical presentation. Laboratory investigations. Imaging studies. Histologic studies. Treatment. Differential Diagnosis of a Noncompressive Myelopathy Peripheral Nervous System Syndromes HIV-Associated Neuropathies Inflammatory Demyelinating Polyneuropathies Laboratory investigations. Electrophysiologic studies. Nerve biopsy. Treatment. Distal Sensory Polyneuropathy Clinical presentation. Laboratory investigations. Electrophysiologic studies. Nerve and skin biopsy. Treatment. Nucleoside Neuropathy Clinical presentation. Laboratory investigations. Treatment. Mononeuritis Multiplex Clinical presentation. Laboratory investigations. Electrophysiologic studies. Nerve biopsy. Treatment. Progressive Polyradiculopathy Clinical presentation. Laboratory investigations. Electrophysiologic studies. Nerve biopsy. Treatment. Diffuse Infiltrative Lymphocytosis Syndrome–Associated Neuropathy Clinical presentation. Electrophysiologic studies. Nerve biopsy. Treatment. Amyotrophic Lateral Sclerosis–Like Syndrome Musculoskeletal Syndromes HIV-Associated Myopathies Muscular Complications From Therapies in HIV Opportunistic Infections and Tumor Infiltrations Seizures Temporal Trends and Aging in Neurologic Manifestations of HIV Infection Key References References 126 Human Immunodeficiency Virus Infection in Women Epidemiology Epidemiology in the United States Risk Factors for and Changing Patterns of Transmission Racial and Ethnic Disparities in HIV Incidence Age Patterns in Women Living With HIV in the United States HIV Care Continuum Among Women Worldwide Epidemiology Disproportionate Impact on Young Women Update on Perinatal Transmission Rates Risk Factors for HIV Transmission to Women Worldwide Regional Variation in HIV Incidence and the Impact on Women AIDS-Related Mortality and Its Impact on Women and Families Transmission and Acquisition in Women and Preventive Strategies Heterosexual Transmission Efficiency of Transmission Factors Associated With Transmission Impact of Hormonal Contraception on HIV Transmission and Acquisition Sexually Transmitted Infections HIV Infection Within the Genital Tract Strategies to Prevent Heterosexual Transmission Barrier Methods Treatment of Sexually Transmitted Infections Microbicides Treatment as Prevention Preexposure Prophylaxis in Women Reproductive Care of Women Living With HIV Conception for Women Living With or at Risk of HIV Reproductive Desires Fertility Issues Safe Conception Contraception for Women With or at Risk of HIV Impact of Hormonal Contraceptives on HIV Progression Drug-Drug Interactions Between ART and Hormonal Contraceptives HIV and Pregnancy Guidelines on Use of Antiretroviral Agents in Pregnant HIV-Infected Women Perinatal Transmission: Timing, Risk Factors, and Strategies to Eliminate Timing of Perinatal Transmission Risk Factors for Perinatal Transmission Use of Antiretroviral Drugs to Decrease Perinatal Transmission Potential Mechanisms of Antiretroviral Drugs to Reduce Perinatal Transmission Impact of Pregnancy on HIV Infection Impact of HIV Infection on Pregnancy Outcomes Antepartum Care of Women Living With HIV HIV-Infected Pregnant Women Who Have Never Received Antiretroviral Drugs HIV-Infected Pregnant Women Who Are Currently Receiving Antiretroviral Therapy Stopping Antiretroviral Therapy During Pregnancy HIV-Infected Pregnant Women Who Have Previously Received Antiretroviral Therapy but Are Not Currently Receiving Medication Monitoring of the Woman and Fetus During Pregnancy Teratogenicity Intrapartum Antiretroviral Therapy Care of Newborn Postpartum Follow-Up of HIV-Infected Women Clinical Manifestations of HIV Infection in Women Opportunistic Processes and Nongynecologic Malignancies Gynecologic Infections and Disease Human Papillomavirus Infections Cervical Infection Extracervical Infection Prevention of Human Papillomavirus Infection Vaginal Infections Bacterial Vaginosis Vulvovaginal Candidiasis Trichomonal Vaginitis Pelvic Inflammatory Disease Genital Ulcer Disease Sex Differences in HIV Infection and Treatment Responses Sex Differences in Clinical Progression Virologic and Immunologic Differences Between Men and Women Off ART Sex Differences in the HIV Reservoir and Possible Impact on Cure Strategies Sex Differences in Responses to Antiretroviral Therapy and Pharmacokinetics Treatment Outcomes Pharmacokinetics Sex Differences in Comorbidities Sex Differences in Aging Inclusion of Women in Clinical Research Key References References 127 Pediatric Human Immunodeficiency Virus Infection Short View Summary Current Epidemiology of Domestic Pediatric and Adolescent HIV Infection Remaining Challenges in Domestic Pediatric HIV Infection Elimination of New Pediatric HIV Infection Maternal Determinants of Mother-to-Child Transmission Postpartum Mother-to- Child Transmission Elimination of Mother-to- Child Transmission Management of the HIV-Exposed Infant General Measures Antiretroviral Agents Diagnosis of HIV Infection in the HIV-Exposed Infant Adolescent HIV Infection Prevention of Infection Issues in the Care of Aging HIV-Infected Youth Disclosure of the HIV Diagnosis Care Refusal and Low Adherence Among HIV-Infected Youth Transition of HIV-Infected Youth From the Pediatric Care Model to the Adult Care Model Adult Complications of Perinatal HIV Infection Key References References 128 Antiretroviral Therapy for Human Immunodeficiency Virus Infection Short View Summary Antiretroviral Agents Nucleoside and Nucleotide Reverse-Transcriptase Inhibitors Lamivudine-Emtricitabine Abacavir Tenofovir Integrase Strand Transfer Inhibitors Raltegravir Elvitegravir Dolutegravir Bictegravir Nonnucleoside Reverse-Transcriptase Inhibitors Efavirenz Rilpivirine Protease Inhibitors Boosted Atazanavir Boosted Darunavir Ritonavir Drugs Used Less Commonly or of Historical Interest Nucleoside and Nucleotide Reverse-Transcriptase Inhibitors (See Fig. 128.2) Zidovudine Stavudine Didanosine Nonnucleoside Reverse Transcriptase Inhibitors (See Fig. 128.4) Nevirapine Etravirine Protease Inhibitors (See Fig. 128.5) Saquinavir Indinavir Nelfinavir Fosamprenavir Lopinavir/Ritonavir Tipranavir Entry Inhibitors Enfuvirtide Maraviroc Ibalizumab Initiating Antiretroviral Therapy When to Begin Therapy? What to Begin With? Dual-NRTI Backbone Initial INSTI-, NNRTI-, or PI-Based Therapy Initial Integrase Inhibitor–Based Therapy Initial PI-Based Regimens Alternative NNRTI-Based Regimens Triple NRTI and Four-Drug Therapy Two-Drug Therapy Interrupting Therapy Laboratory Testing During Antiretroviral Therapy CD4 T-Cell Counts HLA-B*5701 Screening Plasma Viral Load Monitoring HIV Drug Resistance Testing Determining HIV Coreceptor Usage Changing Therapy Special Circumstances Preexposure Prophylaxis Postexposure Prophylaxis Occupational HIV Exposures Nonoccupational HIV Exposures Conclusions and Future Directions Key References References 129 Management of Opportunistic Infections Associated With Human Immunodeficiency Virus Infection Short View Summary Immunologic Monitoring Spectrum of Opportunistic Pathogens Infections Due to Pathogens That Are Not Opportunistic Management of Antiretroviral Therapy for Patients With Acute Opportunistic Infection Drug Interactions Prevention of Opportunistic Infections Antiretroviral Therapy Empirical Versus Specific Therapy Management of Specific Opportunistic Infections Pneumocystis jirovecii Pneumonia Toxoplasma gondii Herpes Simplex Virus and Varicella-Zoster Virus Cytomegalovirus Epstein-Barr Virus and Human Herpesvirus 6 and 7 JC Virus Encephalitis (Progressive Multifocal Leukoencephalopathy) Candida Species Cryptococcus neoformans, Histoplasma capsulatum, and Coccidioides immitis/Coccidioides posadii Bacterial Pneumonia Mycobacterium Species Infection Mycobacterium tuberculosis Mycobacterium avium Complex Enteric Pathogens: Salmonella, Shigella, and Campylobacter Species and Clostridiodes difficile (formerly Clostridium difficile) Cryptosporidium, Cystoisospora, Cyclospora, and Microsporida Species Treponema pallidum Bartonella Species Kaposi Sarcoma and Human Herpesvirus 8 Viral Hepatitis Key References References P Miscellaneous Syndromes 130 Chronic Fatigue Syndrome (Systemic Exertion Intolerance Disease) Short View Summary History Epidemiology Etiology and Pathogenesis Role of Infection Role of the Autonomic Nervous System Role of the Immune System Role of the Central Nervous System Role of the Genome Clinical Manifestations Laboratory Findings Management General Principles Pharmacologic Therapy Nonpharmacologic Therapy Summary Key References References III Infectious Diseases and Their Etiologic Agents A Viral Diseases 131 Biology of Viruses and Viral Diseases History Virus Structure and Classification Virus-Cell Interactions Attachment Penetration and Disassembly Genome Replication Release Cell Killing Antiviral Drugs Virus-Host Interaction Entry Spread Tropism Persistent Infections Viruses and Cancer Viral Virulence Determinants Host Responses to Infection Key References References i DNA Viruses a. Poxviridae 132 Orthopoxviruses Vaccinia (Smallpox Vaccine), Variola (Smallpox), Monkeypox, and Cowpox Short View Summary Background Morphology and Chemical Structure Pathogenesis Vaccinia (Smallpox Vaccine) Immunity Resulting From Vaccination Complications Resulting From Vaccination Vaccinia Virus as a Zoonosis Variola (Smallpox) Monkeypox Pathogenesis Clinical Manifestations Diagnosis Epidemiology and Control Cowpox Clinical Manifestations Newly Described Orthopoxviruses Orthopoxvirus Laboratory Diagnostics Therapy Key References References 133 Other Poxviruses That Infect Humans: Parapoxviruses (Including Orf Virus), Molluscum Contagiosum, and Yatapoxviruses Short View Summary Parapoxviruses Morphology and Composition of the Agent Pathogenesis and Immune Response Clinical Manifestations Diagnosis Epidemiology Therapy Molluscum Contagiosum Description of the Agent Pathogenesis and Pathology Clinical Manifestations Diagnosis Epidemiology and Control Therapy Yatapoxviruses Tanapox Pathophysiology and Clinical Manifestations Diagnosis Epidemiology and Control Yaba Monkey Tumor Virus Clinical Manifestations Key References References b. Herpesviridae 134 Introduction to Herpesviridae Classification Genome Structure and Proteins Virus Replication Virus Latency and Reactivation Pathogenesis Epidemiology Clinical Syndromes Immunity Oncogenesis Diagnosis Therapy Prevention Key References References 135 Herpes Simplex Virus Short View Summary Description of Virus Microbiology Virus Structure Virus Replication Molecular Features of Latency Dynamics of Herpes Simplex Virus Latency and Reactivation Epidemiology Herpes Simplex Virus Type 1 Herpes Simplex Virus Type 2 Herpes Simplex Virus Type 2 Risk Factors Transmission Pathogenesis Primary Infection Ganglionic Cell–Mediated Immunity Mucosal Cell–Mediated Immunity Innate Host Factors Impacting Pathogenesis and Disease Severity Cell-Mediated Host Factors Impacting Pathogenesis and Disease Severity Humoral Host Factors Impacting Pathogenesis and Disease Severity Spectrum of Diseases Caused by Herpes Simplex Virus Orofacial Herpes Simplex Virus Infection Complications of Oral Herpes Simplex Virus Type 1 Genital Herpes Simplex Virus Infection Local Complications of Genital Herpes Simplex Virus Infection Aseptic Meningitis, Transverse Myelitis, and Sacral Radiculopathy Extragenital Lesions Disseminated Infection Superinfection Recurrent Mucocutaneous Herpes Simplex Virus Infections Frequency of Reactivation and Recurrence Subclinical Herpes Simplex Virus Type 2 Shedding Herpetic Whitlow Herpes Gladiatorum Eye Infections Herpes Simplex Virus Encephalitis Visceral and Pulmonary Herpes Simplex Virus Infections Genital Herpes Simplex Virus Infection in HIV-Infected Patients Increased Risk of HIV-1 Acquisition in Herpes Simplex Virus Type 2–Infected Patients Impact of Herpes Simplex Virus Type 2 Infection on HIV Transmission Probability From Coinfected Patients Herpes Simplex Virus Infections in Immunocompromised Hosts Not Infected With HIV Neonatal Herpes Prevention Measures for Neonatal Herpes Herpes Simplex Virus Infection in Pregnancy Clinical Course of Genital Herpes in Pregnancy Surveillance Strategies for Neonatal Transmission of Herpes Simplex Virus Prevention of Herpes Simplex Virus Acquisition in Pregnancy by Use of Antiviral Agents Diagnosis of Active Herpes Simplex Virus Infections Diagnosis of Established Herpes Simplex Virus Infections Overview of Therapies for Herpes Simplex Virus Infections Treatment of Primary Genital Herpes Simplex Virus Infection Suppressive Therapy for Persistent Genital Herpes Simplex Virus Infection Episodic Therapy for Persistent Genital Herpes Simplex Virus Infection Therapy for Severe Herpes Simplex Virus Infection Prophylaxis of Herpes Simplex Virus in Immunocompromised Hosts and Development of Drug Resistance Treatment of Drug-Resistant Herpes Simplex Virus Novel Antiviral Agents for Herpes Simplex Virus Type 1 and Type 2 Infections Counseling and Prevention Herpes Simplex Virus Vaccines Key References References 136 Chickenpox and Herpes Zoster (Varicella-Zoster Virus) Short View Summary Historical Overview Pathogen and Its Replication Epidemiology of Varicella-Zoster Virus Infections Chickenpox Herpes Zoster Pathogenesis Clinical Manifestations Chickenpox Chickenpox in the Immunocompromised Patient Herpes Zoster Diagnosis Therapy Prevention Key References References 137 Cytomegalovirus Short View Summary Microbiology Virus Structure Replication Persistence in the Host Host Interaction and Responses Pathogenesis of HCMV Infection Pathogenesis of HCMV in the Setting of Immunosuppression and Virus Dissemination Pathogenesis of Diseases That Lack a Direct Relationship to Levels of Virus Replication Routes of Transmission and Sources of HCMV Infection Clinical Manifestations Infection in the Immunocompetent Host (Infectious Mononucleosis) Transfusion-Acquired Infection Association With Inflammatory Bowel Disease HCMV Infections in the Immunocompromised Host HCMV Infections in Solid-Organ Transplant Recipients (See Also Chapter 308) HCMV Infection and Allograft Survival and Function in Solid-Organ Transplantation HCMV Infections in Hematopoietic Stem Cell Transplant Recipients (See Also Chapter 307) Congenital HCMV Infection Diagnosis of HCMV Infections Quantitative Nucleic Acid Amplification Technologies Antigen Detection Virus Culture Serology Diagnosis of Congenital Infections Therapy of HCMV Infections (see also Chapter 46) Prophylaxis and Preemption Viral Resistance Therapy of Congenital Infections Passive Immunotherapies for the Prevention and Treatment of HCMV Infections Vaccines for the Prevention and Treatment of HCMV Infections Key References References 138 Epstein-Barr Virus (Infectious Mononucleosis, Epstein-Barr Virus–Associated Malignant Diseases, and Other Diseases) Short View Summary History Description of Epstein-barr Virus Physical Properties Life Cycle Latent Infection and Growth Transformation Epstein-Barr Virus Drives B Cells to Proliferate Epstein-Barr Virus Genome Is Circularized in Latent Infection and Expresses a Subset of Viral Genes Functions of Epstein-Barr Virus Genes Expressed in Latent Infection Patterns of Epstein-Barr Virus Gene Expression Vary in Different Malignancies Lytic Infection Epidemiology Serum Antibody Prevalence Incidence of Infection Methods of Spread Public Health Impact Pathogenesis Host Immune Response Immune Response Controls Epstein-Barr Virus Infection and Is the Cause of Mononucleosis Symptoms Cellular Response to Epstein-Barr Virus Humoral Response to Epstein-Barr Virus Heterophile Antibodies Generated Early During Primary Epstein-Barr Virus Infection Have No Known Role in Pathogenesis Epstein-Barr Virus Immune Evasion Histopathologic Findings Clinical Manifestations Infectious Mononucleosis (Primary Infection) Spectrum of Illness Symptoms and Signs Complications Dermatologic Complications Hematologic Complications Splenic Rupture Neurologic Manifestations Hepatic Manifestations Renal Manifestations Cardiac Manifestations Pulmonary Manifestations Death Clinical Course Genetic Disorders Associated With Severe Epstein-Barr Virus Disease X-linked Genetic Predispositions to Severe Epstein-Barr Virus Disease Autosomal Genetic Predispositions to Severe Epstein-Barr Virus Disease Genetic Disorders That Predispose to Severe Epstein-Barr Virus Disease and Other Infections Chronic Active Epstein-Barr Virus Infection Epstein-Barr Virus–Associated Hemophagocytic Lymphohistiocytosis Oral Hairy Leukoplakia Epstein-Barr Virus–Associated Malignant Diseases Lymphoproliferative Disease Burkitt Lymphoma Hodgkin Lymphoma Diffuse Large B-Cell Lymphoma Nasopharyngeal Carcinoma Gastric Carcinoma Other Malignant Diseases Multiple Sclerosis and Other Autoimmune Diseases Laboratory Diagnosis Infectious Mononucleosis Hematologic Findings Heterophile Antibodies Epstein-Barr Virus–Specific Antibodies Viral Capsid Antigen Antibodies Early Antigen Antibodies Epstein-Barr Nuclear Antigen Antibodies Culture of Epstein-Barr Virus Epstein-Barr Virus Viral Load Other Laboratory Abnormalities Posttransplant Lymphoproliferative Disease Nasopharyngeal Carcinoma Central Nervous System Lymphoma in Acquired Immunodeficiency Syndrome Differential Diagnosis of Infectious Mononucleosis Heterophile-Negative Infectious Mononucleosis Caused by Epstein-Barr Virus Cytomegalovirus as a Cause of Heterophile-Negative Infectious Mononucleosis Primary Human Immunodeficiency Virus Infection Group A Streptococcal Pharyngitis Hepatitis A, B, or C Toxoplasmosis and Other Infections Therapy Infectious Mononucleosis Supportive Antiviral Agents Corticosteroids Lymphoproliferative Disease Epstein-Barr Virus Targeted Therapy in Associated Malignant Diseases Oral Hairy Leukoplakia Prevention Public Health Measures Vaccine Key References References 139 Human Herpesvirus Types 6 and 7 (Exanthem Subitum) Short View Summary Human Herpesvirus Type 6 History Description of the Virus Epidemiology Pathogenesis Clinical Manifestations Infantile Fever and Seizures Exanthem Subitum (Roseola Infantum or Sixth Disease) Other Neurologic Symptoms Associated With HHV-6 Infectious Mononucleosis Other Complications in Healthy Persons Congenital Infection Infection in the Immunocompromised Host Laboratory Diagnosis Healthy Persons Immunocompromised Persons Therapy Human Herpesvirus Type 7 History Description of the Virus Epidemiology Pathogenesis Clinical Manifestations Laboratory Diagnosis Therapy Key References References 140 Kaposi Sarcoma–Associated Herpesvirus (Human Herpesvirus 8) Short View Summary History Discovery of KSHV Classification and Biology Virus Description KSHV Entry Into Cells Lytic Virus Infection Latent Virus Infection KSHV Gene Expression in Latent Infection Possible Paracrine Effects of Lytic Virus Infection Laboratory Infection Models Pathogenesis Suppression of Immunity as a Factor Leading to KSHV Malignancy KSHV and Inflammation Epidemiology Assays to Identify KSHV Infection Geographic Variance of KSHV Seroprevalence in Contrast to Other Herpesviruses KSHV Transmission Clinical Manifestations Primary Infection Kaposi Sarcoma Four Epidemiologic Forms of KS Diagnosis KSHV Viral Load Measurement Genetic Predisposition to KS Treatment KS-Associated IRIS After Institution of Antiretroviral Therapy Primary Effusion Lymphoma Multicentric Castleman Disease KSHV Inflammatory Cytokine Syndrome Other Syndromes Therapy and Prevention Key References References 141 Herpes B Virus Short View Summary History Description of the Virus Epidemiology Pathogenesis Clinical Manifestations Laboratory Diagnosis After Exposure Postexposure Evaluation and Prophylaxis Diagnosis of Herpes B Virus Disease Therapy Prevention Key References References c. Adenoviridae 142 Adenoviruses Short View Summary Description of the Pathogen Interactions With the Host Epidemiology Clinical Syndromes Respiratory Tract Disease Ocular Disease Gastrointestinal Tract Disease Genitourinary Tract Disease Central Nervous System Disease Other Clinical Syndromes Infections in Immunocompromised Patients Hematopoietic Stem Cell Transplant Recipients Solid-Organ Transplant Recipients Human Immunodeficiency Virus/Acquired Immunodeficiency Syndrome Patients Diagnosis Therapy Prevention Adenoviruses as Vectors for Gene Therapy and Vaccination Key References References d. Papillomaviridae 143 Papillomaviruses Short View Summary Virology Epidemiology Incidence and Prevalence Transmission Association Between Human Papillomavirus and Malignant Diseases Pathogenesis Clinical Manifestations Cutaneous Warts Epidermodysplasia Verruciformis Anogenital Warts Recurrent Respiratory Papillomatosis Other Human Papillomavirus Infections Diagnosis Therapy Cutaneous Warts Anogenital Warts Other Warts Prevention and Vaccination Vaccination Key References References 144 JC, BK, and Other Polyomaviruses: Progressive Multifocal Leukoencephalopathy (PML) Short View Summary Virology History Epidemiology Genome Receptors and Cell Entry JC Virus BK Virus New Human Polyomaviruses Progressive Multifocal Leukoencephalopathy and Other JC Virus–Associated Syndromes Epidemiology Pathogenesis Clinical Manifestations Classic Progressive Multifocal Leukoencephalopathy Progressive Multifocal Leukoencephalopathy–Immune Reconstitution Inflammatory Syndrome JC Virus Granule Cell Neuronopathy JC Virus Encephalopathy JC Virus Meningitis Diagnosis Imaging Brain Biopsy Cerebrospinal Fluid Polymerase Chain Reaction Assay Prognosis Therapy Nephropathy and Other BK Virus–Associated Diseases Epidemiology Pathogenesis Clinical Manifestations Nephropathy Ureteral Stenosis Hemorrhagic Cystitis Infections Outside the Renal System Diagnosis Urine Polymerase Chain Reaction Assay Renal Biopsy Plasma Polymerase Chain Reaction Assay Prognosis Prevention and Therapy Nephropathy Ureteral Stenosis Hemorrhagic Cystitis Key References References e. Hepadnaviridae 145 Hepatitis B Virus Short View Summary Overview Historical Background and Classification Virology Attachment, Entry, and Hepatotropism Viral Genome Transcription Translation Replication HBx Morphogenesis and Assembly Natural History and Pathogenesis of Disease Natural History Pathogenesis Acute Hepatitis B Chronic Hepatitis B Hepatocellular Carcinoma Epidemiology of Hepatitis B Routes of Transmission Clinical Manifestations and Prognosis Acute Hepatitis B Fulminant Hepatitis Chronic Hepatitis B Precore or HBe-Negative Mutants Prognosis of Untreated Chronic Hepatitis B Hepatocellular Carcinoma Extrahepatic Manifestations of Hepatitis B Clinical Manifestations and Natural History in Special Hosts Individuals With Human Immunodeficiency Virus Infection Hepatitis B After Liver Transplantation Hepatitis B After Other Types of Transplantation Coinfection With Hepatitis C Screening and Diagnosis of HBV Infection Acute Hepatitis Past Hepatitis B Infection and Vaccination Chronic Hepatitis B Infection Measures of Hepatitis B Replication Isolated anti-HBc Management of Hepatitis B Chronic Hepatitis B Acute Hepatitis B Selection of Patients for Treatment Interferon Nucleoside and Nucleotide Analogues Lamivudine Adefovir Entecavir Telbivudine Tenofovir Disoproxil Fumarate (TDF) and Tenofovir Alafenamide (TAF) Other Agents and Combination Therapy Viral Resistance Monitoring and Treatment Duration of Nucleos(t)ide Therapy Management in Special Populations Liver Transplantation Human Immunodeficiency Virus Recipients of Immunosuppressive Therapies Treatment of Hepatitis B Virus During Pregnancy Other Management Issues in Chronic Hepatitis B Hepatitis A Vaccination Screening and Vaccination of Contacts Surveillance for Hepatocellular Carcinoma Prevention of Hepatitis B Virus Infection Active Immunization Indications for Vaccination Dose Regimen Efficacy Efficacy in Patients With Human Immunodeficiency Virus Infection Efficacy in End-Stage Renal Disease Durability of Response Postexposure Immunoprophylaxis Prevention of Perinatal Transmission Hepatitis B Surface Antigen Escape Mutants Acknowledgments Key References References 146 Hepatitis Delta Virus Short View Summary Hepatitis Delta Virus Hepatitis Delta Antigen Hepatitis D Virus Life Cycle Hepatocyte Entry RNA Genome and Replication Pathogenesis Epidemiology Diagnosis Transmission and Clinical Manifestations Treatment Transplantation Key References References f. Parvoviridae 147 Human Parvoviruses, Including Parvovirus B19V and Human Bocaparvoviruses Short View Summary Parvovirus B19 Virology Pathogenesis Epidemiology Prevalence and Incidence Mechanism and Routes of Transmission Clinical Manifestations Erythema Infectiosum Arthropathy Transient Aplastic Crisis Pure Red Cell Aplasia Virus-Associated Hemophagocytic Syndrome Fetal Infection (Hydrops Fetalis and Miscarriage) Other Disease Manifestations Immune Response Diagnosis Therapy Prevention and Vaccination Other Human Parvoviruses Human Dependoparvoviruses Human Bocaparvoviruses Parv4 Human Protoparvoviruses Key References References ii. RNA Viruses • a. Reoviridae 148 Orthoreoviruses and Orbiviruses Short View Summary Orthoreoviruses Background and Epidemiology Clinical Disease Respiratory Tract Manifestations Gastrointestinal and Hepatobiliary Manifestations Central Nervous System Manifestations Reovirus as an Oncolytic Agent Orbiviruses Background and Epidemiology Clinical Disease Clinical Manifestations of Specific Agents Kemerovo Virus Antigenic Complex Oklahoma Tick Fever Orungo Virus Lebombo Virus Changuinola Virus African Horse Sickness Virus Diagnosis Key References References 149 Coltiviruses (Colorado Tick Fever Virus) and Seadornaviruses Short View Summary Coltiviruses Colorado Tick Fever Virus Epidemiology Clinical and Laboratory Features Diagnosis Treatment and Prevention Salmon River Virus Eyach Virus Seadornaviruses Banna Virus Acknowledgment References 150 Rotaviruses Short View Summary History and Overview Classification and Impact Discovery Path From Basic Science to Vaccine Introduction Viral Structure and Replication Structural Overview Inactivation Priming for Infectivity Receptor Binding and Human Susceptibility Internalization Into Target Cells Conformational Changes Linked to Membrane Perforation and Escape Transcription From Double-Layered Particles and Preferential Translation of Viral mRNA Genome Packaging and Assortment Viroplasm Formation Reverse Genetics Systems Outer Capsid Assembly Clinical Manifestations Typical Clinical Illness Clinical Laboratory Findings Spectrum of Disease Severity Extraintestinal Manifestations and Disease in Immunodeficiency Other Disease Associations Proposed Links to Autoimmunity Pathogenesis Pathologic Findings in Infection Human Intestinal Enteroid Infection Model Correlations Between Pathologic and Clinical Findings Physiology of Rotavirus Diarrhea Viral Enterotoxin The Enteric Nervous System in Rotavirus Gastroenteritis Serology and Classification Overview Rotavirus Groups Binomial Serology of Group A Rotaviruses Genetic Classification of Group A Strains Diversity of Group A Strains Epidemiology Universality of Infection Mortality and Global Impact Health Care Utilization and Impact in High-Income Countries Seasonality Transmission Risk Factors for Disease Veterinary and Zoonotic Disease Immunity Protection From Reinfection by Natural Infection Protection by Antibody Protection by Breastfeeding Role of Serotype in Protection Heterotypic Neutralization by Antibodies Mechanisms of Neutralization by Antibodies Protection by Antibodies Against VP6 and Intracellular Neutralization Mouse Studies on the Roles of T-Cell–Mediated, Antibody-Mediated, and Innate Immunity in Viral Clearance and Protection From Reinfection Evidence for the Role of Innate Immunity From Studies in Human Cells Diagnosis Clinical Utility of Virologic Diagnosis Diagnosis by Antigen Detection Diagnosis by Reverse-Transcriptase Polymerase Chain Reaction Diagnosis by Electron Microscopy, Electrophoresis, and Viral Culture Future Diagnostic Trends Therapy Overview Rehydration Zinc Supplementation Antidiarrheal Agents Antiemetics Probiotics Passive Oral Immunotherapy and Immunoprophylaxis Immunization Overview RotaShield and History of Intestinal Intussusception Rotarix RotaTeq Contraindications for Allergic Reactions, Severe Combined Immunodeficiency Disease, and Elevated Risk of Intestinal Intussusception Porcine Circovirus in Vaccine Manufacturing Reduction in Rotavirus Disease Burden Resulting From Immunization Reduced Vaccine Efficacy in Low-Income Settings Benefits of Rotavirus Immunization in Low-Income Settings Global Rotavirus Vaccine Introduction Regional Rotavirus Vaccines: Lanzhou Lamb Rotavirus Vaccine, Rotavac, Rotasiil, and Rotavin-M1 Nonreplicating Rotavirus Vaccine Candidates Acknowledgments Key References References b. Togaviridae 151 Alphaviruses (Chikungunya, Eastern Equine Encephalitis) Short View Summary History Mechanism of Replication Phylogeny Epidemiology Encephalitis-Causing Alphaviruses Eastern Equine Encephalitis Viruses Western Equine Encephalitis Viruses Venezuelan Equine Encephalitis Viruses Alphaviruses Causing Fever, Polyarthritis, and Rash Chikungunya Virus O’nyong-Nyong Virus Sindbis Virus Ross River Virus and Barmah Forest Virus Mayaro Virus Pathogenesis Encephalitis Fever, Arthralgia, and Rash Clinical Manifestations Alphaviruses Causing Encephalitis Alphaviruses Causing Fever, Polyarthritis, and Rash Diagnosis Therapy and Prevention Key References References 152 Rubella Virus (German Measles) Short View Summary Epidemiology Transmission of Rubella Maintenance of Immunity to Rubella Pathogenesis Clinical Manifestations Postnatal Rubella Complications of Postnatal Rubella Congenital Rubella Syndrome Diagnosis Therapy Vaccination Against Rubella Complications of Vaccination Efficacy of Vaccination Effects of Rubella Vaccine on the Fetus Key References References c. Flaviviridae 153 Flaviviruses (Dengue, Yellow Fever, Japanese Encephalitis, West Nile Encephalitis, Usutu Encephalitis, St. Louis Encephalitis, Tick-Borne Encephalitis, Kyasanur Forest Disease, Alkhurma Hemorrhagic Fever, Zika) Short View Summary History Yellow Fever Dengue Japanese Encephalitis Virus West Nile Virus Usutu Virus St. Louis Encephalitis Virus Tick-Borne Encephalitis Virus Alkhurma Hemorrhagic Fever Virus Kyasanur Forest Disease Virus Zika Virus Pathogens Epidemiology Yellow Fever Dengue Japanese Encephalitis West Nile Encephalitis St. Louis Encephalitis Tick-Borne Encephalitis Alkhurma Hemorrhagic Fever Kyasanur Forest Disease Zika Pathogenesis Yellow Fever Dengue and Dengue Hemorrhagic Fever Encephalitis Congenital Malformations and Guillain-Barré Syndrome Clinical Manifestations Yellow Fever Dengue Fever and Dengue Hemorrhagic Fever Japanese Encephalitis West Nile Virus Fever and West Nile Encephalitis St. Louis Encephalitis Tick-Borne Encephalitis (Including Powassan Encephalitis) Alkhurma Hemorrhagic Fever Kyasanur Forest Disease Zika Virus Infection Laboratory Diagnosis Prevention and Therapy Yellow Fever Dengue and Dengue Hemorrhagic Fever Zika Virus Infection Flavivirus Encephalitis Other Flavivirus Infections Murray Valley Encephalitis Rocio Encephalitis Omsk Hemorrhagic Fever Less Commonly Recognized Flavivirus Infections Acknowledgments Key References References 154 Hepatitis C Short View Summary Non-a, Non-B Viral Hepatitis and Hepatitis C Hepatitis C Virus Virology and Classification Organization of the Hepatitis C Virus Genome Nontranslated RNA Segments Polyprotein Structural Proteins p7 and NS2 Proteins Nonstructural Proteins Involved in RNA Replication Viral Replication Genetic Diversity Quasispecies Variation Hepatitis C Virus Genotypes Viral Tropism Experimental Models Autonomously Replicating Viral Replicons and Genome-Length RNAs Propagation of Virus in Cell Cultures Animal Models Natural History and Pathogenesis Viral Persistence Innate Immunity Humoral Immunity Cellular Immunity Disease Progression Hepatic Fibrosis Human Immunodeficiency Virus and Hepatitis C Virus Infection Clinical Manifestations of Hepatitis C Virus Infection Acute Hepatitis C Fulminant Hepatitis C Chronic Hepatitis C Hepatocellular Carcinoma Extrahepatic Manifestations of Hepatitis C Virus Infection Diagnosis Laboratory Assessment of Hepatitis C Virus Infection Screening Serology RNA Detection Core Antigen Detection Genotype Other Laboratory Testing Clinical Application of Tests for Hepatitis C Virus Liver Fibrosis Staging Liver Biopsy Noninvasive Blood Markers of Hepatic Fibrosis Radiographic Tests Approach to Staging Liver Disease Epidemiology of Hepatitis C Prevalence of Hepatitis C Virus Prevalence of Hepatitis C Virus in Those With HIV Incidence and Transmission of Hepatitis C Virus Biologic Basis of Transmission Percutaneous Transmission Nosocomial Infection Sexual Transmission Maternal-Infant Transmission Transmission Cofactors Treatment of Chronic Hepatitis C Treatment Responses Virologic Responses Histologic and Clinical Responses to Therapy Medications Interferon-α Ribavirin Protease Inhibitors Nucleos(t)ide and Nonnucleoside Polymerase Inhibitors NS5A Protein Inhibitors Treatment of Chronic Hepatitis C History and Progress (Fig. 154.9) Initial Treatment of Chronic Hepatitis C Virus Infection Genotype 1 Genotype 2 Genotype 3 Genotype 4 Genotypes 5 and 6 Response Indicators Antiviral Resistance Re-treatment of Chronic Hepatitis C Virus Infection Failure of Interferon and Ribavirin With or Without NS3/4 Protease Inhibitor Failure of Non-NS5A Inhibitor, Sofosbuvir-Containing Regimens Failure of Direct-Acting Antiviral Regimens Containing NS5A Inhibitors Adverse Reactions Recommended Treatments for Chronic Hepatitis C as of 2018 Selection of Patients for Treatment Initial Treatment and Re-treatment of Patients With Chronic Hepatitis C, Including Those With HIV Infection Treatment of Acute Hepatitis C Prevention Preexposure Prevention Postexposure Prevention Hepatitis C Virus Elimination World Health Organization Goals Current State: Hepatitis C Virus Treatment Cascade From Modeling to Real-World Examples Acknowledgments Key References References d. Coronaviridae 155 Coronaviruses, Including Severe Acute Respiratory Syndrome (SARS) and Middle East Respiratory Syndrome (MERS) Short View Summary History Community-Acquired Respiratory Coronaviruses, Severe Acute Respiratory Syndrome, and Middle East Respiratory Syndrome Gastrointestinal Coronaviruses and Toroviruses Description of the Pathogens Epidemiology CAR Coronaviruses MERS Coronavirus SARS Coronavirus Gastrointestinal Coronaviruses Pathogenesis CAR Coronaviruses MERS Coronavirus SARS Coronavirus Clinical Manifestations CAR Coronaviruses MERS Coronavirus SARS Coronavirus Gastrointestinal Coronaviruses Neurologic Syndromes Laboratory Diagnosis CAR Coronaviruses MERS Coronavirus SARS Coronavirus Therapy Prevention Key References References e. Paramyxoviridae 156 Parainfluenza Viruses Short View Summary Virology Pathogenesis Epidemiology Clinical Manifestations Pediatric Disease Adult Disease Parainfluenza Virus in Immunocompromised Patients Diagnosis Therapy Prevention Key References References 157 Mumps Virus Short View Summary History Virology Epidemiology Pathogenesis Pathology Clinical Manifestations Complications Immunology Diagnosis Differential Diagnosis Therapy Prevention Key References References 158 Respiratory Syncytial Virus Short View Summary History Virology Classification Viral Structure and Characteristics Laboratory Properties Infection in Animals Epidemiology Distribution and Seasonal Occurrence Antigenic Variation Epidemiology Manifestations Prevalence and Incidence Pathogenesis Immunity and Pathogenesis of Disease Maternally Derived Immunity Innate Immunity Adaptive Immunity Clinical Manifestations Infection Among Young Children (Bronchiolitis and Other Lower Respiratory Tract Illnesses) Otitis Media Infections Among Older Children Infections Among Adults Complications Patients at High Risk for Severe Infection Immunocompromised Patients Acute Complications in Infants Long-Term Complications Diagnosis Therapy Prevention Infection Prevention Prophylaxis Immunization Acknowledgments Key References References 159 Human Metapneumovirus Short View Summary Virology Pathogenesis and Host Response Epidemiology Clinical Manifestations Children Adults Immunocompromised Hosts Diagnosis Viral Culture Immunofluorescence Assay Reverse-Transcriptase Polymerase Chain Reaction Serology Treatment Prevention Key References References 160 Measles Virus (Rubeola) Short View Summary Description of the Pathogen Morphology Chemical and Antigenic Composition Growth of Measles Virus in Tissue Culture Host Range Epidemiology Spread of Infection Other Diseases Associated With Measles Virus Pathogenesis Immunity Clinical Manifestations Complications Special Considerations Modified Measles Atypical Measles Immunocompromised Patients Pregnant Women and Their Offspring Persons With Tuberculosis Occurrence in Adults Diagnosis Prevention Therapy Key References References 161 Zoonotic Paramyxoviruses Short View Summary Virology Classification Structure and Molecular Biology Nipah and Hendra Viruses Menangle Virus Emergence of Henipaviruses Nipah Virus Epidemiology Reservoirs and Intermediate Hosts Clinical Manifestations Laboratory Abnormalities Diagnostic Tests Pathology Therapy Prevention Hendra Virus Epidemiology Reservoirs and Intermediate Hosts Clinical Manifestations Laboratory Abnormalities Diagnostic Tests Pathology Therapy Prevention Menangle Virus Epidemiology Pathogenesis Clinical Manifestations and Diagnostic Tests Key References References f. Rhabdoviridae 162 Vesicular Stomatitis Virus and Related Vesiculoviruses (Chandipura Virus) Short View Summary Virology Classification and Structure Molecular Biology Epidemiology Epizootic Enzootic Animal Disease Clinical Manifestations Diagnosis Host Response Therapy Prevention and Vaccination Key References References 163 Rabies (Rhabdoviruses) Short View Summary Virology Classification Epidemiology Human Rabies Transplant-Associated Rabies Animal Rabies Composition Pathogenesis Pathology Immune Responses Clinical Manifestations Human Rabies Incubation Period Prodromal Symptoms Encephalitic (Furious) Rabies Paralytic (Dumb) Rabies Nonneurologic Findings Animal Rabies Diagnosis Differential Diagnosis Prevention Preexposure Prophylaxis Postexposure Prophylaxis Treatment Key References References g. Filoviridae 164 Marburg and Ebola Virus Hemorrhagic Fevers Short View Summary Virus Characterization Epidemiology Marburg Hemorrhagic Fever Ebola Hemorrhagic Fever Natural History Clinical Manifestations and Diagnosis Pathogenesis Countermeasures Prevention Treatment Key References References h. Orthomyxoviridae 165 Influenza Viruses, Including Avian Influenza and Swine Influenza Short View Summary History The Viruses Classification Virology Epidemiology and Disease Impact Disease Impact Epidemic Influenza Transmission Pandemic Influenza Antigenic Variation Antigenic Drift Antigenic Shift Emergence of Pandemic Viruses From Birds Human Infections With H5 Viruses Human Infections With H7 Viruses Human Infections With H9 Viruses Factors Controlling Host Range Emergence of Pandemic Viruses From Swine Clinical Findings Uncomplicated Influenza Complications of Influenza Pulmonary Complications Primary Influenza Viral Pneumonia Secondary Bacterial Pneumonia Pulmonary Complications in Immunosuppressed Patients Other Pulmonary Complications Nonpulmonary Complications Myositis Cardiac Complications Toxic Shock Syndrome Central Nervous Complications Reye Syndrome Pathogenesis Cellular Pathogenesis Virus Shedding Cytokine Response Histopathology Pathophysiology Host Response Antibody Responses Systemic Antibody Responses Mucosal Antibody Responses Cellular Responses Diagnosis Clinical Diagnosis Laboratory Diagnosis Polymerase Chain Reaction–Based Tests Rapid Nucleic Acid Amplification Tests Rapid Influenza Diagnostic Tests Virus Isolation Role of Viral Diagnosis in Clinical Decision Making Prevention Currently Available Vaccines Egg-Grown Inactivated Influenza Vaccines (IIV-3, IIV-4) Cell Culture–Derived Inactivated Vaccine (ccIIV-4) Recombinant Hemagglutinin Expressed in Insect Cells (rIV-4) High-Dose Egg-Grown Inactivated Vaccine (HD-IIV3) MF-59 Adjuvanted Inactivated Influenza Vaccine (aIIV-3) Intranasal Live-Attenuated Influenza Vaccine (LAIV-4) Safety Inactivated Vaccines Live-Attenuated Vaccines Immune Responses to Vaccination Intramuscular Protein Vaccines Intranasal Live-Attenuated Vaccine Markers of Immune Responsiveness Efficacy (Results of Randomized Prospective Studies) Intramuscular Protein Vaccines Intranasal Live Vaccines Effectiveness (Results of Observational Studies) Effects of Prior Vaccination Comparisons of Live and Inactivated Vaccines Secondary Protection Maternal Immunization Recommendations for Vaccine Use Vaccines for Pandemic Influenza Strategies for More Broadly Protective Vaccines Antiviral Agents (Also See Chapter 45) M2 Inhibitors: Amantadine and Rimantadine Mechanism of Action and Activity Pharmacology and Side Effects Efficacy Drug Resistance Neuraminidase Inhibitors: Zanamivir, Oseltamivir, and Peramivir Mechanism of Action and Activity Pharmacology and Side Effects Efficacy Drug Resistance Antiviral Agents in Development Recommendations for Therapeutic Use of Antivirals Chemoprophylaxis Seasonal Prophylaxis Family Prophylaxis Outbreak Prophylaxis Key References References i. Bunyaviridae 166 California Encephalitis, Hantavirus Pulmonary Syndrome, Hantavirus Hemorrhagic Fever With Renal Syndrome, and Bunyavirus Hemorrhagic Fevers Short View Summary Virology Structure, Replication, and Antigenic Relationships Epidemiology Ecology and Distribution California Encephalitis Viruses Rift Valley Fever Crimean-Congo Hemorrhagic Fever Hantaviruses Transmission to Humans California Encephalitis Virus Group Rift Valley Fever Crimean-Congo Hemorrhagic Fever Hantaviruses Clinical Manifestations California Encephalitis Virus Group Rift Valley Fever Crimean-Congo Hemorrhagic Fever Hantaviruses Hemorrhagic Fever With Renal Syndrome Hantavirus Pulmonary Syndrome Diagnosis California Encephalitis Riff Valley Fever and Congo-Crimea Hemorrhagic Fever Viruses Hantaviruses Therapy Prevention Other Bunyavirales of Concern Jamestown Canyon Virus Oropouche Virus Toscana Virus Ngari Virus Severe Fever With Thrombocytopenia Syndrome Virus Heartland Virus Acknowledgment Key References References j. Arenaviridae 167 Lymphocytic Choriomeningitis Virus, Lassa Virus, and the South American Hemorrhagic Fevers (Arenaviruses) Short View Summary Viral Characterization Epidemiology Lymphocytic Choriomeningitis Lassa Fever Other African Arenaviruses South American Hemorrhagic Fevers Other Arenaviruses Pathogenesis Rodents Nonhuman Primates Humans Clinical Manifestations Lymphocytic Choriomeningitis Virus Lassa Fever South American Hemorrhagic Fevers Intrauterine Infection Diagnosis Treatment Prevention Key References References k. Retroviridae 168 Human T-Cell Leukemia Viruses (HTLV-1, HTLV-2) Short View Summary Structure and Molecular Organization gag, pro, pol, and env TAX HBZ and APH REX Other Proteins Encoded by the pX Region Biology Laboratory Detection Virus Isolation Serologic Assays and Antigen Detection Nucleic Acid Detection Serologic Epidemiology Geographic Distribution of Prevalence Demographic Patterns in Prevalence Incidence Molecular Epidemiology HTLV-1 HTLV-2 HTLV-3 and HTLV-4 Routes of Transmission Mother-to-Child Transmission Sexual Transmission Parenteral Transmission Immunology of HTLV Infection Humoral Immune Responses Cellular Immunity Clinical Manifestations of HTLV Infections HTLV-1–Associated Malignancies HTLV-Associated Myelopathy Other Diseases Associated With HTLV-1 Diseases Associated With HTLV-2 Therapy Asymptomatic HTLV-1 and HTLV-2 Carriers Adult T-Cell Leukemia HTLV-1–Associated Myelopathy Prevention Conclusion Acknowledgment Key References References 169 Human Immunodeficiency Viruses Short View Summary Overview of Human Immunodeficiency Virus and Acquired Immunodeficiency Syndrome Origin and Classification of Human Retroviruses Viral Transmission and Life Cycle Biology of Transmission Replication Cycle: Cell Entry and Integration Replication Cycle: Virus Expression and Production of New Virions The Virion Genomic Organization Virion Structural Proteins Gag Proteins Viral Enzymes pol Gene Products Protease Reverse Transcriptase Integrase Envelope Glycoproteins and Viral Fusion Virus-Cell Fusion Viral Regulatory and Accessory Genes Virus Regulation and the Long Terminal Repeat Virus-Host Interactions Viral Receptors, Chemokines, Receptors, and Tropism Pathogenesis, T-Cell Depletion, and Viral Load Viral Variation: Genetic and Phenotypic Variation Malignancies and Human Immunodeficiency Virus Conclusion Acknowledgment Key References References l. Picornaviridae 170 Introduction to the Human Enteroviruses and Parechoviruses Enteroviruses Virology Physical Characteristics Molecular Biology Pathogenesis and Immunity in Enteroviral Infections Pathogenesis Viral Mutation During Natural Infection Immunity and the Immune Response Epidemiology of Enteroviral Infections Age and Socioeconomic Status Molecular Epidemiology Transmission Incidence of Infection and Illness Incubation Period and Period of Communicability Laboratory Diagnosis of Enteroviral Infections Viral Isolation Nucleic Acid Amplification Testing and Genomic Sequencing Serology Treatment and Prevention of Enteroviral Infections Parechoviruses Virology Virus Types Viral Diagnosis Epidemiology Key References References 171 Poliovirus Short View Summary History Pathophysiology Virology Pathogenesis Clinical Manifestations Incubation Period Clinical Manifestations of Infection Spinal Paralytic Poliomyelitis Bulbar Paralytic Poliomyelitis Polioencephalitis Complications Risk Factors Differential Diagnosis Laboratory Diagnosis Prognosis Therapy Postpoliomyelitis Syndrome Poliovirus Immunization Poliovirus Vaccines Inactivated Poliovirus Vaccine Live-Attenuated Poliovirus Vaccine Monovalent and Bivalent Oral Poliovirus Vaccines Vaccine-Associated Paralytic Poliomyelitis Use of Poliomyelitis Vaccines in the Developing World Poliomyelitis in Developing Nations and Global Eradication Vaccine-Derived Poliomyelitis Viruses Key References References 172 Coxsackieviruses, Echoviruses, and Numbered Enteroviruses (EV-A71, EVD-68, EVD-70) Short View Summary Central Nervous System Infections Acute Viral Meningitis Clinical Manifestations Laboratory Diagnosis Differential Diagnosis Management and Prognosis Encephalitis Acute Flaccid Paralysis/Myelitis and Other Neurologic Complications Exanthems Rubelliform and Morbilliform Exanthems Roseoliform Exanthems Herpetiform Exanthems Hand-Foot-and-Mouth Disease Petechial Exanthems and Other Cutaneous Manifestations Acute Respiratory Disease (EV-D68) Herpangina Clinical Manifestations Differential Diagnosis Myositis Pleurodynia Epidemiology Pathogenesis Clinical Manifestations Diagnosis Management and Prognosis Other Skeletal Myositis Myopericarditis Etiology and Pathogenesis Clinical Manifestations Diagnostic Virology Management Course and Prognosis Dilated Cardiomyopathy Coxsackievirus and Echovirus Disease in the Newborn Epidemiology Pathophysiology Clinical Manifestations Myocarditis Hepatitis Pneumonia Diagnosis and Differential Diagnosis Management Chronic Meningoencephalitis in Agammaglobulinemic and Other Immunocompromised Patients Clinical Manifestations Prophylaxis and Therapy Infections in Other Immunocompromised Patients Acute Hemorrhagic Conjunctivitis Epidemiology Patterns of Transmission Clinical Manifestations Complications Differential Diagnosis Laboratory Diagnosis Treatment and Prevention Illnesses in Which the Etiologic Role of Enteroviruses Is Minor or Poorly Defined Gastrointestinal Diseases Other Diseases Diabetes Mellitus Enterovirus A71 Infections Key References References 173 Parechoviruses Short View Summary Historical Background Virology Epidemiology Clinical Manifestations Undifferentiated Febrile Illness/Sepsis Syndrome Central Nervous System Infections Meningitis Encephalitis Acute Flaccid Paralysis Gastrointestinal Disease Hemorrhage-Hepatitis Syndrome Necrotizing Enterocolitis Acute Gastroenteritis Respiratory Disease Miscellaneous Clinical Associations Diagnosis Therapy and Prevention Key References References 174 Hepatitis A Virus Short View Summary History Classification and Physicochemical and Biologic Properties of Hepatitis a Virus Structure Resistance to Physical and Chemical Agents Genome and Proteins Antigenic Composition and Viral Diversity Biology of Hepatitis A Virus in Cell Culture Host Range Epidemiology Modes of Transmission Person to Person Foodborne and Waterborne Bloodborne Vertical Worldwide Disease Patterns Epidemiology in the United States Potential Sources of Infection Specific Groups and Settings of Infection International Travel International Adoption and Migrant and Refugee Populations Users of Injection and Noninjection Drugs and People Experiencing Homelessness Men Who Have Sex With Men Transfusion and Health Care Settings Foodborne and Waterborne Hepatitis A Institutions Including Daycare for Children and Facilities for Persons With Developmental Disabilities Pathogenesis Incubation Period Site of Viral Replication Pathology Manifestations Signs and Symptoms Complications Therapy and General Management Laboratory Diagnosis Immunity Prevention Infection Prevention and Control Passive Immunization Active Immunization Recommendations for Prevention Postexposure Prophylaxis Preexposure Prophylaxis Disease-Control Strategies Routine Vaccination of Children Vaccination of Persons at Increased Risk of Hepatitis A Infection or Severe Consequences Men Who Have Sex With Men Users of Illicit Drugs International Travelers Close Contacts of Newly Arriving International Adoptees Recipients of Blood or Plasma-Derived Products Persons With Chronic Liver Disease Other Groups and Settings Hepatitis A Vaccination During Outbreaks Directions for the Future Acknowledgment Key References References 175 Rhinovirus Short View Summary Virology Classification Structure Genomic Organization Epidemiology Age Seasonality Pathogenesis Inflammatory Responses Nasal Fluid Production Transmission Clinical Manifestations of Common Cold Complications Acute Bacterial Sinusitis Acute Bacterial Otitis Media Asthma Exacerbation of Chronic Bronchitis Lower Respiratory Tract Infections Infections in Immunocompromised Patients Diagnosis Virus Isolation in Tissue Culture Molecular Techniques Antigen Detection Neutralizing Antibody Assays Therapy Symptomatic Therapy Antivirals Interferon Prevention Virus Inactivation on Skin Acid Inactivation of Virus Intercellular Adhesion Molecule 1 Receptor Blockade Vaccines Acknowledgment Key References References iii Caliciviridae and Other Gastrointestinal 176 Noroviruses and Sapoviruses (Caliciviruses) Short View Summary History Virology Taxonomy Genome Organization Antigenic Characterization Epidemiology Antigenic Variation Seroprevalence Transmission of Infection Environmental Contamination Pathogenesis Immune Response Clinical Manifestations Diagnosis Clinical Diagnosis Laboratory Diagnosis Therapy Prevention Vaccines Key References References 177 Astroviruses and Picobirnaviruses Short View Summary Astroviruses Virology Classification Structure Genomic Organization Epidemiology Pathogenesis Clinical Manifestations Immune Responses Diagnosis Therapy Prevention Picobirnaviruses Key References References iv Unclassified Viruses 178 Hepatitis E Virus Short View Summary A Brief History Genetics Natural History of Hepatitis E Burden of Disease Geographic Distribution Transmission Clinical Presentation Acute Hepatitis E Chronic Hepatitis E Extrahepatic Manifestations Special Considerations Pregnancy Solid Organ Transplantation Coinfections Diagnostic Evaluation General Principles Serologic Evaluation Molecular Diagnosis Histopathology Therapeutic Strategies Acute Hepatitis E Chronic Hepatitis E Prevention General Measures Vaccination Key References References B Prion Diseases 179 Prions and Prion Disease of the Central Nervous System (Transmissible Neurodegenerative Diseases) Short View Summary Brief History of Prion Disease Research Molecular Biology and Pathophysiology of Prion Diseases The Prion Protein Infectious Prions Propagation of Prions In vitro Synthesis of Prions Other Macromolecules Contributing to Prion Propagation Species Barrier to Transmission of Prion Diseases Prion Strains Transmission by Oral Exposure Neurodegeneration in Prion Disease Yeast Prions Prion-Like Behavior of Other Neurodegenerative Diseases Human Prion Diseases Classification and Epidemiology of Human Prion Disease Epidemiology of Creutzfeldt-Jakob Disease Sporadic Creutzfeldt-Jakob Disease Epidemiology Clinical Features Strains Familial Prion Disease Overview and Epidemiology Gerstmann-Sträussler-Scheinker Syndrome Fatal Familial Insomnia Long-Duration Genetic Prion Disease Polymorphisms in PRNP Infectiously Acquired Human Prion Disease Kuru Variant Creutzfeldt-Jakob Disease Epidemiology Clinical Features Transmission by Blood Products Neuropathology vCJD Caused by Exposure to BSE Genetics of vCJD Susceptibility Subclinical vCJD Iatrogenic Creutzfeldt-Jakob Disease Transmission Through Dura Mater Grafts Transmission Through Cadaver-Derived Hormones Transmission Through Corneal Transplants Transmission Through Surgical Instruments Inadvertent Surgical Exposure Blood Products and Sporadic CJD CJD in Health Professionals Nosocomial and Iatrogenic Infection Risk Prion Disease in Ruminants Atypical Forms of Bovine Spongiform Encephalopathy Atypical Forms of Scrapie Chronic Wasting Disease Camel Prion Disease Laboratory Diagnosis of Prion Disease Prion Disease Mimics Specific Testing for Prion Disease (RT-QuIC) Supportive Testing for Prion Disease CSF Proteins Brain Imaging Electroencephalography in Creutzfeldt-Jakob Disease Histology of Creutzfeldt-Jakob Disease Tissue Biochemical Tests Genetic Testing and Creutzfeldt-Jakob Disease Prion Disease Therapy Key References References C Chlamydial Diseases 180 Chlamydia trachomatis (Trachoma and Urogenital Infections) Short View Summary Chlamydial Biology Antigenic and Genetic Diversity Pathogenesis Immunity Laboratory Diagnosis Nucleic Acid Amplification Tests Antigen Detection and Nucleic Acid Hybridization Isolation in Cell Culture Cytologic Diagnosis Rapid Tests Serology Clinical Manifestations Trachoma Treatment Oculogenital Disease in Adults Inclusion Conjunctivitis Urogenital Infections Urogenital Infections in Men Urethritis Epididymitis and Prostatitis Sexually Reactive Arthritis Urogenital Infections in Women Cervicitis and Urethritis Pelvic Inflammatory Disease Infertility and Ectopic Pregnancy Pregnancy Complications Extragenital Infections Proctitis (Rectal Infections) Oropharyngeal Infections Other Infections Treatment of Genital and Ocular Infections in Adults Perinatal Infections Neonatal Inclusion Conjunctivitis Infant Pneumonia Diagnosis of Neonatal Inclusion Conjunctivitis and Infant Pneumonia Prevention and Treatment of Infant Infections Chlamydial Infections in Prepubertal Children Lymphogranuloma Venereum Classic LGV LGV Proctitis and Proctocolitis Diagnosis of Lymphogranuloma Venereum Treatment of Lymphogranuloma Venereum Prevention Strategies Key References References 181 Psittacosis (Due to Chlamydia psittaci) Short View Summary Epidemiology Clinical Manifestations and Differential Diagnostic Considerations Laboratory Findings Pathologic Findings Diagnosis Therapy Prevention Key References References 182 Chlamydia pneumoniae Short View Summary History Microbiology Laboratory Testing for Chlamydia pneumoniae Cell Culture Antigen Detection Single and Multiplex Nucleic Acid Amplification Tests Serologic Testing Epidemiology Clinical Manifestations Therapy Chlamydia pneumoniae and Chronic Disease in Humans Chlamydia pneumoniae and Asthma Therapy Chlamydia pneumoniae and Other Chronic Diseases Chlamydia pneumoniae and Atherosclerosis Chlamydia pneumoniae and Multiple Sclerosis Key References References D Mycoplasma Diseases 183 Mycoplasma pneumoniae and Atypical Pneumonia Short View Summary History Microbiology Epidemiology Immunology and Resistance Innate Immunity Adaptive Immunity Cold Agglutinins Resistance and Susceptibility to Infection Pathology Disease Syndromes Respiratory Illnesses Other Illnesses Dermatologic Syndromes Raynaud Phenomenon Cardiac Syndromes Neurologic Syndromes Musculoskeletal, Renal, and Hematologic Syndromes Diagnosis Cold Agglutinins Culture Detection of Mycoplasma pneumoniae–Specific Antibodies Detection of Mycoplasma pneumoniae–Specific Antigens Detection of Mycoplasma pneumoniae–Specific Nucleic Acids Treatment Prevention Infection Control Vaccination Key References References 184 Genital Mycoplasmas: Mycoplasma genitalium, Mycoplasma hominis, and Ureaplasma Species Short View Summary Taxonomy and Microbiology Epidemiology Clinical Manifestations Ureaplasmas Mycoplasma hominis Mycoplasma genitalium Laboratory Diagnosis Therapy Key References References E Rickettsioses, Ehrlichioses, and Anaplasmoses 185 Introduction to Rickettsioses, Ehrlichioses, and Anaplasmoses Bacteriology History and Emerging Diseases Pathophysiology Genetics Epidemiology Clinical Findings Diagnosis Treatment Remaining Questions and Perspectives References 186 Rickettsia rickettsii and Other Spotted Fever Group Rickettsiae (Rocky Mountain Spotted Fever and Other Spotted Fevers) Short View Summary Rocky Mountain Spotted Fever The Pathogen Virulence Factors Epidemiology Pathogenesis Clinical Manifestations Diagnosis Treatment Prevention Other Spotted Fever Group Rickettsioses Boutonneuse Fever (Mediterranean Spotted Fever) Spotted Fevers: Moderate Severity Spotted Fevers: Mild Severity Flea-borne Spotted Fever Diagnosis Treatment Key References References 187 Rickettsia akari (Rickettsialpox) Short View Summary Etiology Epidemiology Clinical Manifestations Diagnosis Therapy References 188 Coxiella burnetii (Q Fever) Short View Summary Pathogen Epidemiology History Zoonotic Sources Transmission Between Humans Incidence Outbreaks Pathogenesis Clinical Manifestations Self-Limited Febrile Illness Pneumonia Radiologic Findings Outcome Laboratory Findings Diagnosis of Acute Q Fever Treatment of Acute Q Fever Monitoring Patients With Acute Q Fever Endocarditis Clinical Manifestations of Endocarditis Diagnosis of Endocarditis Treatment of Q Fever Endocarditis Follow-Up Hepatitis Neurologic Manifestations Q Fever in the Immunocompromised Host Other Manifestations of Q Fever Q Fever in Pregnancy Post–Q Fever Fatigue Syndrome Prevention Vaccination Risk Reduction Key References References 189 Rickettsia prowazekii (Epidemic or Louse-Borne Typhus) Short View Summary Microbiology Epidemiology Louse-Borne Epidemic Typhus Sylvatic Typhus Pathogenesis Clinical Manifestations Louse-Borne Epidemic Typhus Sylvatic Typhus Recrudescent Typhus Diagnosis Treatment Prevention Key References References 190 Rickettsia typhi (Murine Typhus) Short View Summary Microbiology Epidemiology Pathology and Pathogenesis Clinical Manifestations Signs and Symptoms Laboratory Features Diagnosis Treatment and Prevention Key References References 191 Orientia tsutsugamushi (Scrub Typhus) Short View Summary History Definition Ecology and Epidemiology Microbiology Diagnosis Immune Response Therapy Prevention Key References References 192 Ehrlichia chaffeensis (Human Monocytotropic Ehrlichiosis), Anaplasma phagocytophilum (Human Granulocytotropic Anaplasmosis), and Other Anaplasmataceae Short View Summary Etiology Epidemiology and Epizootiology of Human Monocytotropic Ehrlichiosis Epidemiology and Epizootiology of Human Granulocytic Anaplasmosis Pathogenesis and Pathology Human Monocytotropic Ehrlichiosis Human Granulocytotropic Anaplasmosis Clinical Manifestations Human Monocytotropic Ehrlichiosis Signs and Symptoms Course Diagnosis Differential Diagnosis Ehrlichiosis Caused by Ehrlichia ewingii and Ehrlichia muris Human Granulocytotropic Anaplasmosis Signs, Symptoms, and Course Diagnosis Treatment and Prevention Candidatus Neoehrlichia Mikurensis Human Infections Prevention of Ehrlichiosis and Anaplasmosis Sennetsu Neorickettsiosis Key References References F Bacterial Diseases 193 Introduction to Bacteria and Bacterial Diseases Classification of Bacteria Variation in Bacterial Infections Polymorphism and Bacterial Infection Bacteria as “New” Causes for “Old” Diseases Bacterial Evolution Bacteria as Therapeutics Key References References i. Gram-Positive Cocci 194 Staphylococcus aureus (Including Staphylococcal Toxic Shock Syndrome) Short View Summary The Microorganism Habitat Culture and Identification Morphologic Variants Molecular Diagnosis Molecular Typing Pulsed-Field Gel Electrophoresis Multilocus Sequence Typing Spa Typing and Double-Locus Spa-ClfB Typing Pathogenesis Regulation and Virulence Determinants Regulation agr and Other Two-Component Regulatory Systems DNA-Binding Proteins Small RNAs and Endoribonuclease III Role in Pathogenesis Ecologic and Epidemiologic Implication of agr The Journey to Invasive Disease Mucosal and Skin Colonization Host Invasion Contribution of Coagulation Immune Evasion Escaping Phagocytosis Luring Complement Resisting Oxidative Burst Resisting Antimicrobial Peptides Killing Leukocytes Panton-valentine leukocidin. Escaping Cell-Mediated Immunity Producing Biofilm Exfoliative Toxins and Staphylococcal Scalded Skin Syndrome Molecular Pathogenesis of Staphylococcal Scalded Skin Syndrome Clinical Aspects Superantigens Toxic Shock Syndrome Menstrual Toxic Shock Syndrome Nonmenstrual Toxic Shock Syndrome Predisposing Factors Diagnosis Therapy and Prevention Enterotoxins and Food Poisoning Other Implications of Superantigens Genomics and Mobile Genetic Elements Comparative Genomics and Evolution Staphylococcus aureus Cross-Species Jump Between Humans and Animals Pathogenicity and Genomic Islands Resistance Island Staphylococcal Cassette Chromosome mec Antibiotic Resistance β-Lactams Resistance to Penicillin Methicillin-Resistant Staphylococcus aureus Health Care–Associated Versus Community-Acquired Methicillin-Resistant Staphylococcus aureus Mechanism of Methicillin Resistance Glycopeptides Therapeutic Monitoring of Vancomycin in Adult Patients Intermediate Resistance to Glycopeptides Full Resistance to Glycopeptides Daptomycin Protein Synthesis Inhibitors MLSB Antibiotics Drug Efflux Oxazolidinones Quinolones Mechanisms of Resistance Alternative Treatments Alternatives Against Non–Life- Threatening Infections Tigecycline Aminomethylcyclines Quinupristin-Dalfopristin Lipoglycopeptides Alternatives Against Severe Infections Combination Therapy β-Lactams With Improved Penicillin-Binding Protein 2A Affinity Development of Nonantibiotic and Vaccine Strategies Antimicrobial Peptides Virulence Modulation Immunomodulation Antibiotic Resensitization Phage Lysins Phage Therapy Vaccines Clinical Aspects and Epidemiology Clinical Spectrum Risk Factors for Staphylococcus aureus Infection The Burden of Antibiotic Resistance Carriage of Staphylococcus aureus Carriage of Methicillin-Resistant Staphylococcus aureus Preventive Measures to Limit Health Care–Associated Infections Methicillin-Resistant Staphylococcus aureus Infections Clinical Syndromes Skin and Soft Tissues Infections Classification Impetigo Folliculitis Furuncles and Carbuncles Hidradenitis Suppurativa Mastitis Surgical Site Infection Erysipelas, Cellulitis, and Fasciitis Management of Skin and Soft Tissue Infection Bloodstream Infection Community-Onset Bacteremia Nosocomial and Health Care–Associated Bloodstream Infection Management of Staphylococcus aureus Bloodstream Infection Infective Endocarditis Epidemiology Pathogenesis Role of Bacterial Adhesins Role of Platelets Host Defenses and Prevention Clinical Spectrum Vascular Complications Neurologic Complications Diagnosis Management of Staphylococcus aureus Endocarditis Management of Right-Sided Endocarditis in Injection Drug Users Infections of the Central Nervous System Meningitis Spinal Epidural Abscess Pulmonary Infections Epidemiology Clinical Spectrum Therapy Osteoarticular Infections Osteomyelitis Epidemiology Pathogenesis Clinical Features Diagnosis Therapy Native Joint Septic Arthritis Septic Bursitis Prosthetic Joint Infections Pyomyositis Acknowledgment Key References References 195 Staphylococcus epidermidis and Other Coagulase-Negative Staphylococci Short View Summary Microbiology and Ecology Antibiotic Resistance Molecular Epidemiology Pathogenesis Virulence Factors Biofilm Adherence Maturation Dispersal Other Virulence Factors Phenol Soluble Modulins Poly-Gamma-dl-Glutamic Acid Antimicrobial Peptide Resistance Lantibiotics Other Coagulase-Negative Species Epidemiology and Clinical Syndromes Colonization and Transmission Bacteremia Intravascular Catheter Infections Endocarditis Cardiovascular Implantable Electronic Devices Vascular Grafts Orthopedic Prosthetic Device Infections Cerebrospinal Fluid Shunt Infections Surgical Site Infections Peritoneal Dialysis Catheter–Associated Infections and Peritoneal Dialysis–Associated Peritonitis Endophthalmitis Urinary Tract Infection Infections of Genitourinary Prostheses Mastitis and Infections of Breast Implants Miscellaneous Prosthetic Device Infections, Implant Infections, and Other Infections Patient Populations at Increased Risk of Infection With Coagulase-Negative Staphylococci Transplant Patients and Neutropenic Hosts Neonates Burn Patients Non–Staphylococcus epidermidis Species of Coagulase-Negative Staphylococci Staphylococcus haemolyticus Staphylococcus lugdunensis Staphylococcus saprophyticus Other Species of Coagulase-Negative Staphylococci Novel Therapeutic Options for Infections Due to Coagulase-Negative Staphylococci Key References References 196 Classification of Streptococci References 197 Streptococcus pyogenes Short View Summary History Description of the Pathogen Somatic Constituents Extracellular Products Streptococcal Pharyngitis Epidemiology Clinical Manifestations Scarlet Fever Suppurative Complications Nonsuppurative Complications Diagnosis Throat Culture Rapid Antigen Detection Tests Therapy Streptococcal Pyoderma Epidemiology Bacteriology and Immunology Clinical Manifestations Therapy and Prevention Complications Invasive Streptococcal Infections of Skin and Soft Tissues Erysipelas Streptococcal Cellulitis Necrotizing Fasciitis (Streptococcal Gangrene) Diagnosis and Differential Diagnosis Myositis and Myonecrosis Streptococcal Toxic Shock Syndrome Pathogenesis Mechanisms of Shock and Organ Failure Clinical Manifestations Management Source Control Fluid Resuscitation Antimicrobial Therapy Management in the Intensive Care Unit Dialysis and Hemoperfusion Intravenous Immune Globulin Bacteremia Other Streptococcal Infections Prophylaxis and Risk for Secondary Cases of Streptococcal Toxic Shock Syndrome Key References References 198 Nonsuppurative Poststreptococcal Sequelae Short View Summary Rheumatic Fever History Etiology and Pathogenesis Pathologic Findings Epidemiology Clinical Manifestations Diagnosis Therapy and Prognosis Prevention Glomerulonephritis History Etiology and Pathogenesis Pathologic Characteristics Epidemiology Clinical and Laboratory Features Diagnosis Therapy Prevention Prognosis Key References References Additional Reading 199 Streptococcus pneumoniae Short View Summary History Microbiology Epidemiology Pathogenetic Mechanisms Colonization Pneumococcal Capsular Serotypes and Progression From Colonization to Disease Immunologic Mechanisms of Defense Against and Susceptibility to S. pneumoniae Infection Factors That Predispose to Pneumococcal Infection HIV Infection Clinical Syndromes Otitis Media Sinusitis Meningitis Acute Exacerbation of Chronic Bronchitis Pneumonia Overview Pathogenesis Predisposing Factors Symptoms and Physical Findings Radiographic Findings General Laboratory Findings Diagnostic Microbiology Complications Other Infectious Syndromes Noninfectious Syndromes Antibiotic Susceptibility and Resistance Definitions of Antibiotic Susceptibility Mechanisms of Antibiotic Susceptibility and Resistance Prevalence of Resistance Therapy Otitis Media Sinusitis Pneumonia Outpatient Therapy Inpatient Therapy Meningitis Endocarditis Prevention of Pneumococcal Infections Antibody Responses to Pneumococcal Capsular Polysaccharides Pneumococcal Conjugate Vaccine Efficacy in Children Efficacy of 23-Valent Pneumococcal Polysaccharide and 13-Valent Polysaccharide Conjugate Vaccine in Adults Impact of Infant Immunization on Adult Disease Vaccine Protection During HIV Infection Vaccine Recommendations Key References References 200 Enterococcus Species, Streptococcus gallolyticus Group, and Leuconostoc Species Short View Summary Historical Background Microbiology and Taxonomy Colonization, Virulence, and Genomics Epidemiology of Enterococcal Infections Clinical Manifestations of Enterococcal Disease Bacteremia and Endocarditis Urinary Tract Infections Meningitis Intraabdominal and Pelvic Infections Neonatal Infections Skin, Soft Tissue, and Other Infections Therapy and Antimicrobial Resistance Combination of β-Lactam and Aminoglycosides or Cephalosporins Glycopeptides and Lipoglycopeptides Daptomycin Linezolid Tigecycline Quinupristin-Dalfopristin Other Antienterococcal Antimicrobials Streptococcus Gallolyticus (Bovis) Group Leuconostoc Species Key References References 201 Streptococcus agalactiae (Group B Streptococci) Short View Summary Historical Perspective Description Classification and Morphologic Characteristics Identification Serologic Typing Epidemiology and Transmission Asymptomatic Colonization Transmission Incidence and Serotype Distribution of Isolates Pathogenetic Mechanisms Adherence Invasion Bacterial Virulence Factors Host Factors Clinical Manifestations Primary Bacteremia Infections of the Female Genital Tract Infections in Infants Pneumonia Endocarditis Arthritis Osteomyelitis Skin and Soft Tissue Infections Meningitis Urinary Tract Infections Uncommon Manifestations of Infection Recurrent Invasive Group B Streptococcal Infection Diagnosis Treatment Prevention Group B Streptococcal Vaccines Key References References 202 Viridans Streptococci, Nutritionally Variant Streptococci, and Groups C and G Streptococci Short View Summary Overview Microbiology Viridans Streptococci Streptococcus anginosus Group Nutritionally Variant Streptococci: Abiotrophia sp. and Granulicatella spp. Epidemiology Viridans Streptococci and the Streptococcus anginosus Group Nutritionally Variant Streptococci: Abiotrophia sp. and Granulicatella spp. Virulence Viridans Streptococci Streptococcus anginosus Group Nutritionally Variant Streptococci: Abiotrophia sp. and Granulicatella spp. Clinical Manifestations Abscesses: Streptococcus anginosus Group Aseptic Meningitis: Viridans Streptococci Subacute Bacterial Endocarditis: Viridans streptococci, Streptococcus anginosus, and Nutritionally Variant Streptococci Positive Blood Cultures and Nonsterile Body Sites: Viridans Streptococci Therapy: Viridans Streptococci Subacute Bacterial Endocarditis Meningitis: Viridans Streptococci Endophthalmitis: Viridans Streptococci Reactive and Septic Arthritis: Viridans Streptococci, Group C Streptococcus, and Group G Streptococcus Abscesses: Streptococcus anginosus Group Resistance: Viridans Streptococci and Nutritionally Variant Streptococci—Abiotrophia sp. and Granulicatella spp. Groups C and G Streptococci Group C Streptococci Habitat Microbiology Virulence Clinical Manifestations Treatment Group G Streptococci Habitat Microbiology Virulence Clinical Manifestations Treatment Streptococcus suis Viridans-Like Organisms Rothia Pediococcus Key References References 203 Streptococcus anginosus Group Short View Summary Epidemiology Microbiology Molecular Subspecies Phenotypic Characteristics Taxonomy Molecular Diagnostic Methods Pathogenesis Mixed Infections Contribute to Abscess Formation Virulence Factors Cytotoxins Hydrolytic Enzymes Immune Factors Superantigens Resistance to Phagocytosis Clinical Presentations Head and Neck Infections Intracranial Complications of Head and Neck Infections Bacteremia Endocarditis Central Nervous System Infections Intraabdominal Infections Thoracic Infections Pulmonary Complications Therapy Key References References ii. Gram-Positive Bacilli 204 Corynebacterium diphtheriae (Diphtheria) Short View Summary History The Pathogen Epidemiology Pathogenesis Clinical Manifestations Respiratory Tract Diphtheria Anterior Nasal Faucial Laryngeal and Tracheobronchial Cardiac Toxicity Neurologic Toxicity Other Complications Cutaneous Diphtheria Invasive Disease Other Sites Diagnosis Therapy Prevention Key References References 205 Other Coryneform Bacteria, Arcanobacterium haemolyticum, and Rhodococci Short View Summary Coryneform Bacteria Other Than Corynebacterium diphtheriae Taxonomy Microbiology Nonlipophilic, Fermentative Corynebacteria Corynebacterium ulcerans and Corynebacterium pseudotuberculosis Corynebacterium xerosis Corynebacterium striatum Corynebacterium minutissimum Corynebacterium amycolatum Corynebacterium glucuronolyticum Other Nonlipophilic, Fermentative Corynebacteria Nonlipophilic, Nonfermentative Corynebacteria Corynebacterium afermentans subsp. afermentans Corynebacterium auris Corynebacterium pseudodiphtheriticum Corynebacterium propinquum Lipophilic Corynebacteria Corynebacterium jeikeium Microbiology Pathogenicity Treatment Corynebacterium urealyticum Microbiology Pathogenicity Treatment Other Lipophilic Corynebacteria Arcanobacteria Arcanobacterium haemolyticum Microbiology Infections in Humans Treatment Trueperella (Arcanobacterium) pyogenes Trueperella (Arcanobacterium) bernardiae Miscellaneous Coryneform Bacteria Turicella otitidis Arthrobacter Species Brevibacterium Species Dermabacter hominis Rothia dentocariosa and Rothia mucilaginosa Oerskovia and Cellulosimicrobium Species Microbacterium Species Leifsonia aquatica Other medically relevant coryneform bacteria Rhodococci Taxonomy Rhodococcus equi Epidemiology Microbiology Pathogenicity Clinical Manifestations Treatment Other Rhodococcus Species and Related Genera Key References References 206 Listeria monocytogenes Short View Summary Definition Epidemiology Microbiology Pathogenesis Clinical Manifestations Acute Febrile Gastroenteritis Cutaneous Listeriosis Invasive Listeriosis Pregnancy Neonatal Infection Bacteremia Neurolisteriosis Focal Invasive Infection Diagnosis Treatment Prevention Key References References 207 Bacillus anthracis (Anthrax) Short View Summary Epidemiology Microbiology Clinical Manifestations and Diagnosis Cutaneous Anthrax Differential Diagnosis of Cutaneous Anthrax Laboratory Diagnosis of Cutaneous Anthrax Injectional Anthrax Inhalational or Pulmonary Anthrax Diagnosis of Inhalational Anthrax Gastrointestinal Anthrax Anthrax Meningitis Therapy Cutaneous Anthrax Without Systemic Manifestations Cutaneous Anthrax (With Systemic Manifestations), Injectional Anthrax, Inhalational Anthrax, Gastrointestinal Anthrax, and Meningeal Anthrax Management of Pleural Effusion and Ascites Role of Corticosteroids and Management of Severe Edema Anthrax Antitoxin Therapies (Immunotherapeutics) Prevention Anthrax as an Agent of Bioterrorism History of Bacillus anthracis as a Bioterrorist Agent Dissemination of Anthrax as a Bioterrorist Agent Outbreak Characteristics After Use of Anthrax as a Bioterrorist Agent Anthrax Countermeasures Diagnostics Antibiotics Vaccines Antitoxin Immunotherapy Infection Control Remediation (Decontamination) Key References References 208 Bacillus Species and Related Genera Other Than Bacillus anthracis Short View Summary Microbiology Epidemiology Pseudoinfection and Contamination Commercial Uses of Bacillus Species Adherence Properties Clinical Manifestations Food Poisoning Systemic Infections Central Nervous System Infections Respiratory Infections Eye Infections Soft Tissue, Skin, and Muscle Infection Prevention Therapy Key References References 209 Erysipelothrix rhusiopathiae Short View Summary Microbiology Epidemiology Pathogenesis Clinical Manifestations Diagnosis Therapy and Prevention Key References References 210 Whipple Disease Short View Summary Etiology Epidemiology and Pathogenesis Pathology Clinical Features and Diagnosis Therapy and Prognosis Key References References iii. Gram-Negative Cocci 211 Neisseria meningitidis Short View Summary Definition and History Microbiology Biology and Pathogenesis Meningococcal Colonization and Transmission Host Susceptibility Epidemiology Clinical Manifestations and Pathophysiology Meningococcemia Meningitis Rash of Meningococcal Disease Complement Deficiency and Meningococcal Disease (See also Chapter 9) Chronic Meningococcemia Primary (Purulent) Pericarditis Septic Arthritis Respiratory Tract Infections Conjunctivitis Meningococcal Urethritis and Proctitis Complications Family and Community Impact Diagnosis Treatment Antibiotic Therapy Adjunctive Therapy and Supportive Care Prevention Chemoprophylaxis Immunoprophylaxis Immune Correlates of Protection and Meningococcal Polysaccharide Vaccines Meningococcal Conjugate Vaccines Serogroup B Vaccines Duration of Protection Immunologic Memory and Interference Vaccine Population Coverage and Effectiveness Herd Protection and Vaccine Strategies Meningococcal Vaccine Recommendations Adolescents and Adults Infants and Young Children Outbreak Immunoprophylaxis Hajj and Umrah Pilgrimages Eculizumab (Solaris) Future Meningococcal Disease Vaccine Prevention Strategies Key References References 212 Neisseria gonorrhoeae (Gonorrhea) Short View Summary The Organism Description Growth and Cultivation Surface Structures Type IV Pili Outer Membrane Strain Typing Genetics Plasmids Chromosomal Mutations and Transformation Pathobiology of Gonococcal Infection Infection of the Male Urethra Infection of the Lower Female Genital Tract Infection of the Upper Female Genital Tract The Human Immune Response to Neisseria gonorrhoeae Adaptive Immune Response Innate Immune Response Epidemiology Incidence Transmission Antimicrobial Resistance Clinical Manifestations Genital Infection in Men Uncomplicated Infection Localized Complications Uncomplicated Urogenital Infection in Women Rectal Gonococcal Infection Pharyngeal Infection Other Local Manifestations Pelvic Inflammatory Disease Perihepatitis Gonorrhea in Pregnancy Disseminated Gonococcal Infection Neonatal and Pediatric Infections Diagnosis Culture Nucleic Acid Amplification Tests Gram-Stained Smears Other Diagnostic Methods Therapy Uncomplicated Gonorrhea in Adults Initial Single-Dose Treatment Follow-Up of Patients Treated for Uncomplicated Gonorrhea Pelvic Inflammatory Disease Acute Epididymitis Disseminated Gonococcal Infection Gonorrhea in Children Management of Sex Partners Prevention and Control Public Health Strategies Condoms and Microbicides Other Prevention Strategies Key References References 213 Moraxella catarrhalis, Kingella, and Other Gram-Negative Cocci Short View Summary Moraxella Catarrhalis History Microbiology Epidemiology and Respiratory Tract Colonization Pathogenesis Clinical Manifestations Otitis Media Lower Respiratory Tract Infections in Chronic Obstructive Pulmonary Disease Pneumonia in Older Adults Nosocomial Respiratory Tract Infections Sinusitis Bacteremia Therapy Other Neisseria Other Moraxella Kingella History and Microbiology Epidemiology and Respiratory Tract Colonization Clinical Manifestations Skeletal Infections Endocarditis Bacteremia Other Infections Therapy Key References References iv Gram-Negative Bacilli 214 Vibrio cholerae Short View Summary Classification and Genomics Pathogenicity Epidemiology Clinical Manifestations Diagnosis Treatment Immune Responses Prevention and Vaccines Key References References 215 Other Pathogenic Vibrios Short View Summary Vibrio parahaemolyticus Epidemiology Clinical Manifestations Laboratory Findings Differential Diagnosis Therapy Prevention Vibrio vulnificus Clinical Manifestations Differential Diagnosis Therapy Prevention Vibrio alginolyticus Halophilic Vibrios Nonhalophilic Vibrios: Non-O1/O139 Vibrio cholerae and Vibrio mimicus Epidemiology Clinical Manifestations Laboratory Findings Therapy Prevention Key References References 216 Campylobacter jejuni and Related Species Short View Summary Microbiology Epidemiology Pathogenesis and Pathologic Characteristics Immunology Clinical Manifestations Campylobacter jejuni Infections Campylobacter fetus Infections Infection Caused by Other Enteric Campylobacter Species Diagnosis Bacteriologic Studies Molecular Techniques and Immunoassays Direct Examination of Feces Therapy Antibiotic Resistance Resistance to Fluoroquinolones Resistance to Macrolides Prognosis Prevention Key References References 217 Helicobacter pylori and Other Gastric Helicobacter Species Short View Summary Microbiology Epidemiology Pathology and Pathogenesis Clinical Consequences Associated With H. pylori Colonization Gastrointestinal Diseases Acute Acquisition Persistent Colonization Duodenal Ulceration Gastric Ulceration Gastric Carcinoma Gastric Lymphoma Esophageal Diseases Asthma and Related Disorders Metabolic Disorders Idiopathic Thrombocytopenic Purpura Other Inverse Associations Overview of Clinical Consequences Diagnosis Therapy Indications for Treatment Treatment Regimens Benefits and Risks of Antibiotic Therapy Prevention of H. pylori Acquisition Other Gastric Helicobacters Key References References 218 Enterobacteriaceae Short View Summary General Properties Epidemiology Structural and Surface Antigenic Features Inner Membrane Periplasmic Space Peptidoglycan Cell Wall Outer Membrane Other Surface Polysaccharides and Capsules Flagella Pili Virulence Factors Adhesins Toxins and Secretion Systems Lipopolysaccharide and Capsules Iron Acquisition Specific Organisms Escherichia General Clinical Principles Related to Diarrheagenic Escherichia coli Enterotoxigenic Escherichia coli Enteropathogenic Escherichia coli Shiga Toxin–Producing Escherichia coli Including Enterohemorrhagic Escherichia coli Enteroaggregative Escherichia coli Enteroinvasive Escherichia coli Diffusely Adherent Escherichia coli Adherent-invasive Escherichia coli Extraintestinal Pathogenic Escherichia coli Uropathogenic Escherichia coli Neonatal Meningitis–Associated Escherichia coli Sepsis-Associated Escherichia coli Klebsiella Enterobacter Species, Pantoea agglomerans, and Chronobacter sakazakii Serratia Species Citrobacter Species Hafnia alvei Proteus, Providencia, and Morganella Other Genera Acknowledgment Key References References 219 Pseudomonas aeruginosa and Other Pseudomonas Species Short View Summary Microbiology The Pseudomonas aeruginosa Genome Pseudomonas aeruginosa and the Human Microbiota Virulence Factors Pili Type I and II Secretion Systems Type III Secretion Systems Quorum-Sensing Molecules Other Virulence Factors Epidemiology Transmission Dynamics of Pseudomonas aeruginosa and Reservoirs Antimicrobial Resistance Resistance Mechanisms Intrinsic Resistance Decreased Permeability of the Outer Membrane Efflux Pumps Antimicrobial-Modifying Enzymes Acquired Resistance Aminoglycoside-Modifying Enzyme Treatment of Pseudomonas aeruginosa Infections Infections Caused by Pseudomonas aeruginosa Bloodstream Infections Infective Endocarditis Pneumonia Pneumonia Associated With Hospital Exposure Hospital-Acquired (Nosocomial) Pneumonia Hospital-Acquired Pneumonia Among Ventilated Patients Hospital-Acquired Pneumonia Among Nonventilated Patients Health Care–Associated Pneumonia Community-Acquired Pneumonia Cystic Fibrosis Bone and Joint Infections Sternoclavicular Septic Arthritis Septic Arthritis of the Symphysis Pubis Vertebral Osteomyelitis Skull Base Osteomyelitis Osteomyelitis Related to Nail Puncture Wounds Combat-Related Osteomyelitis Antimicrobial Therapy for Arthritis and Osteomyelitis Skin and Soft Tissue Infections Paronychia and Green Nail Syndrome Interdigital Infections Hot Tub Folliculitis Hot Hand-Foot Syndrome Body Piercing Ecthyma Gangrenosum Ear Infections Simple Otitis Externa (Swimmer’s Ear) Malignant Otitis Externa (Necrotizing Otitis Externa) Eye Infections Keratitis Endophthalmitis Urinary Tract Infections Pseudomonas Species Other Than P. aeruginosa of Major Clinical Significance Pseudomonas fluorescens Pseudomonas fulva Pseudomonas luteola Pseudomonas mendocina Pseudomonas mosselii Pseudomonas oryzihabitans Pseudomonas putida Pseudomonas stutzeri Novel Therapeutic Strategies Against P. aeruginosa Infections Key References References 220 Stenotrophomonas maltophilia and Burkholderia cepacia Complex Short View Summary Microbiology Burkholderia cepacia Complex Species Stenotrophomonas Genotypes Pathogenesis Lipopolysaccharides, Adhesion, and Invasion Siderophores and Secreted Enzymes Chronic Infection and Intracellular Survival Biofilm and Quorum Sensing Epidemiology and at-Risk Populations Stenotrophomonas maltophilia Burkholderia cepacia Complex Clinical Manifestations Stenotrophomonas maltophilia Bacteremia and Endovascular Infections Pulmonary Infections Skin and Soft Tissue Infections Head, Neck, and Central Nervous System Infections Genitourinary, Abdominal, and Other Uncommon Infections Burkholderia cepacia Complex Respiratory Infections in Cystic Fibrosis Lung Transplantation Bacteremia and Pneumonia Other Rare Manifestations Therapy Stenotrophomonas maltophilia Burkholderia cepacia Complex Prevention Strategies, Immunization, and Immunotherapy Immunization and Immunotherapy Key References References 221 Burkholderia pseudomallei and Burkholderia mallei Short View Summary Melioidosis History Etiology Epidemiology Transmission Pathogenesis Clinical Manifestations Laboratory Diagnosis Therapy Initial Intensive Therapy Subsequent Eradication Therapy Adjunctive Therapy Prevention Glanders History Etiology Epidemiology, Transmission, and Pathogenesis Clinical Manifestations Laboratory Diagnosis Therapy Prevention Key References References 222 Acinetobacter Species Short View Summary Epidemiology Health Care–Associated Infections Community-Associated Infections Diagnosis Clinical Manifestations Pathogenesis and Antimicrobial Resistance Treatment β-Lactam Antibiotics β-Lactamase Inhibitors Aminoglycosides Tigecycline Polymyxins Combination Treatment Prevention Key References References 223 Salmonella Species Short View Summary Classification and Taxonomy The Genome Microbiology Epidemiology Pathogenesis Interactions With Intestinal Epithelium and Induction of Enteritis Interactions With Macrophages and Systemic Infection Host Response and Immunity Clinical Manifestations Gastroenteritis Enteric Fever Bacteremia and Vascular Infection Salmonellosis and HIV Infection Localized Infections Chronic Carrier State Immunization Against Salmonella Therapy Gastroenteritis Bacteremia Recurrent Salmonella Bacteremia in Persons With HIV Focal Infections Carrier State Prevention and Control Key References References 224 Bacillary Dysentery Short View Summary Microbiology Isolation Techniques Group and Type Identification Invasive Escherichia coli Pathogenesis Communicability and Infectivity Mucosal Invasion and Inflammation Toxigenicity Anatomic Location of Infection Epidemiology Cyclic Patterns of Disease Incidence of Shigellosis by Geography and Host Modes of Spread and Reservoirs in Nature Diagnosis History Physical Examination Laboratory Findings Therapy and Clinical Course Control Environmental Control Immunologic Control Key References References 225 Haemophilus Species, Including H. influenzae and H. ducreyi (Chancroid) Short View Summary Haemophilus influenzae Description of the Pathogen Distinguishing Haemophilus influenzae from Haemophilus haemolyticus Biotypes Serotypes Epidemiology and Respiratory Tract Colonization Colonization in Children Colonization in Adults With Chronic Obstructive Pulmonary Disease Colonization and Conjugate Vaccines Pathogenesis Otitis Media Otitis Media With Effusion Biofilms Exacerbations of Chronic Obstructive Pulmonary Disease Invasive Infections Caused by Haemophilus influenzae Type b Immunity Nontypeable Haemophilus influenzae Haemophilus influenzae Type b Clinical Manifestations of Nontypeable Haemophilus influenzae Otitis Media Exacerbations of Chronic Obstructive Pulmonary Disease Community-Acquired Pneumonia Acute Respiratory Tract Infections in Children in Developing Countries Sinusitis Neonatal and Maternal Sepsis Bacteremia and Invasive Infections Conjunctivitis Clinical Manifestations of Haemophilus influenzae Type b Meningitis Epiglottitis Pneumonia and Empyema Cellulitis Bacteremia Without Localized Disease Septic Arthritis Clinical Manifestations of Non–Type b Encapsulated Haemophilus influenzae Diagnosis Nontypeable Haemophilus influenzae Haemophilus influenzae Type b Therapy Nontypeable Haemophilus influenzae Haemophilus influenzae Type b Chemoprophylaxis for Haemophilus influenzae Type b Active Immunization Against Haemophilus influenzae Type b Haemophilus influenzae Biogroup aegyptius Haemophilus ducreyi Description of the Pathogen Epidemiology Pathogenesis and Immune Response Clinical Manifestations Diagnosis Therapy Other Haemophilus Species Description of the Pathogens Clinical Manifestations Therapy Key References References 226 Brucellosis (Brucella Species) Short View Summary History Microbiology Epidemiology Pathogenesis Immune Response Clinical Manifestations Complications Skeletal System Nervous System Genitourinary Tract Cardiovascular System Gastrointestinal System Hepatobiliary System Respiratory System Hematologic Complications Cutaneous Lesions Ocular Lesions Pregnancy Diagnosis Treatment Prevention Key References References 227 Francisella tularensis (Tularemia) Short View Summary History Microbiology Virulence Other Francisella Species Epidemiology Distribution Incidence Transmission Pathogenesis Immunity Clinical Manifestations Ulceroglandular and Glandular Tularemia Oculoglandular Tularemia Pharyngeal Tularemia Typhoidal Tularemia Pneumonic Tularemia Secondary Skin Manifestations Francisella tularensis subsp. novicida and Francisella philomiragia Infections Clinical Recognition of a Bioterrorism Event Complications and Outcome Diagnosis Routine Cultures and Pathology Serologic Diagnosis Investigational Diagnostic Assays Therapy Antibiotic Treatment Pregnant and Immunosuppressed Patients Surgical Treatment Immunotherapy Therapy for Tularemia After a Bioterrorism Event Prevention Vaccination Antibiotic Prophylaxis Antibiotic Prophylaxis After a Tularemia Bioterrorism Event Key References References 228 Pasteurella Species Short View Summary Description of the Pathogen Epidemiology Pathogenesis Clinical Manifestations Skin and Soft Tissue Infections Bone and Joint Infections Central Nervous System Infections Bacteremia and Endocarditis Respiratory Tract Infections Intraabdominal Infections Other Pasteurella Infections Therapy, Prevention, and Prognosis Key References References 229A Plague (Yersinia pestis) Short View Summary History Microbiology Epidemiology Natural Cycles Transmission to Humans Pathogenesis Clinical Manifestations Bubonic Plague Septicemic Plague Pneumonic Plague Other Syndromes Laboratory Findings Diagnosis Therapy Antimicrobial Agents Supportive Therapy Prevention Infection Control Chemoprophylaxis Vaccination Environmental Control Bioterrorism Mass Prophylaxis Occupational Exposure Environmental Persistence Acknowledgments Key References References 229B Yersinia enterocolitica and Yersinia pseudotuberculosis Short View Summary Microbiology Epidemiology Clinical Manifestations Postinfectious Complications Pathogenesis Diagnosis Treatment Prevention Acknowledgment Key References References 230 Bordetella pertussis Short View Summary History Description of Pathogen Pathogenesis Epidemiology Prevaccine Era Vaccine Era Current Issues Regarding Resurgence of Pertussis Carrier State Clinical Presentation Young Children Infants and Adults Complications Diagnosis Culture Molecular Diagnosis Serology Direct Fluorescent Antibody Therapy Antimicrobial Agents Supportive Care Prevention Immunization Acellular Pertussis Vaccines Vaccination Schedules Vaccination of Health Care Workers Protection of Infants Vaccination During Pregnancy Neonatal Vaccination Chemoprophylaxis Pertussis in Schools and Daycare Centers Future Directions Key References References 231 Rat-Bite Fever Short View Summary Streptobacillus Moniliformis Bacteriology Epidemiology Pathophysiology Clinical Manifestations Diagnosis Therapy and Prevention Spirillum Minus Bacteriology Epidemiology, Pathogenesis, and Pathology Clinical Manifestations Diagnosis and Therapy Key References References 232 Legionnaires’ Disease and Pontiac Fever Short View Summary History The Etiologic Agent Microbial Ecology Pathogenesis Overview Legionella pneumophila Virulence Factors Virulence Factors and Pathogenesis of Other Legionella Species Epidemiology Incubation Period and Contagiousness Patterns and Rates of Disease and Mortality Risk Factors Modes of Transmission Outbreak Investigation Environmental Decontamination for Outbreaks Clinical Presentation Legionnaires’ Disease Extrapulmonary Infections Pontiac Fever Laboratory Diagnosis Therapy and Response to Therapy Prevention Immunization and Chemoprophylaxis Engineering Modifications and Maintenance Environmental Cultures for Legionella Bacteria Key References References 233 Capnocytophaga Short View Summary Taxonomy Pathogenesis and Clinical Manifestations Human Oral-Associated Species Infections Associated With Zoonotic Species Epidemiology Diagnosis and Laboratory Identification Therapy Prevention Key References References 234 Bartonella, Including Cat-Scratch Disease Short View Summary Background and Classification of Bartonella Species Epidemiology of the Common Human-Pathogenic Bartonella Species Bartonella bacilliformis Epidemiology Bartonella quintana Epidemiology Bartonella henselae Epidemiology Epidemiology of Other Bartonella Species Associated With Human Infection Clinical Manifestations of the Common Human Pathogenic Bartonella Species: B. Bacilliformis, B. Henselae, and B. Quintana (Table 234.2) Bartonella Bacilliformis Clinical Manifestations: Oroya Fever and Verruga Peruana Bartonella henselae and Bartonella quintana: Clinical Manifestations Depend on the Infecting Bartonella Species and Immune Status of Host Bartonella henselae and Bartonella quintana: Bacteremic Illness Bartonella henselae and Bartonella quintana: Endocarditis Other Bartonella Species: Endocarditis and Bacteremia Bartonella henselae and Bartonella quintana Infections in Immunocompromised Patients: Bacillary Angiomatosis/Bacillary Peliosis Bartonella henselae: Cat-Scratch Disease Cat-Scratch Disease Background Typical Cat-Scratch Disease Musculoskeletal Manifestations of Cat-Scratch Disease Atypical Manifestations of Cat-Scratch Disease Encephalopathy Complicating Cat-Scratch Disease Ocular Manifestations of Cat-Scratch Disease Differential Diagnosis of Cat-Scratch Disease Bartonella Infections in Solid-Organ Transplant Recipients Background/Risk Factors for Acquisition of Bartonella in Solid-Organ Transplant Recipients Clinical Features of Bartonella Infection in Solid-Organ Transplant Recipients Diagnosis of Bartonella Infections in Solid-Organ Transplant Recipients Pathologic Findings and Relation to Duration of Time Posttransplant Prognosis for Solid-Organ Transplant Recipients With Bartonella Infection Cellular and Molecular Pathogenesis Associated With Bartonella Infections Laboratory Diagnosis of Bartonella Infections Direct Examination of Blood Smears and Histopathologic Specimens Specimen Collection and Handling for Culture Culture of Bartonella Species Identification of Bartonella Species Molecular Methods for Bartonella Identification and Characterization Serologic Testing for Detecting Infection With Bartonella Species Antimicrobial Susceptibility Testing of Bartonella Isolates Treatment and Prevention of Bartonella Infections Treatment of Bartonella bacilliformis Infections Treatment of Bartonella Infections in the Immunocompromised Host Treatment of Bartonella Bacteremia and Endocarditis Treatment of Cat-Scratch Disease Treatment of Neuroretinitis, Encephalopathy, Osteomyelitis, and Parenchymal Cat-Scratch Disease Prevention of Bartonella Infections Key References References 235 Klebsiella granulomatis (Donovanosis, Granuloma Inguinale) Short View Summary Biology of Causative Organism Geographic Distribution and Epidemiology Clinical Manifestations Diagnosis Therapy Acknowledgment Key References References 236 Other Gram-Negative and Gram-Variable Bacilli Short View Summary Glucose Fermenters Actinobacillus and Aggregatibacter Species Aeromonas Species Cardiobacterium Species Chromobacterium Species Dysgonomonas Species Kingella Species Neisseria animaloris and Neisseria zoodegmatis Plesiomonas shigelloides Glucose Nonfermenters or Weak Fermenters Achromobacter and Alcaligenes Species Chryseobacterium and Elizabethkingia Species Comamonas and Delftia Species Eikenella Species Flavobacterium and Myroides Species Ochrobactrum Species Oligella Species Pseudomonas Species Ralstonia and Cupriavidus Species Rhizobium (Formerly Agrobacterium) Species Roseomonas Species and Other “Pink-Pigmented” Gram-Negative Bacilli Shewanella Species Sphingobacterium Species Sphingomonas Species Weeksella and Bergeyella Species Centers for Disease Control and Prevention Groups Gardnerella and Mobiluncus Species Key References References v. Spirochetes 237 Syphilis (Treponema pallidum) Short View Summary History Etiology Epidemiology Pathogenesis Pathologic Features Natural Course of Untreated Syphilis Clinical Manifestations Primary Syphilis Secondary Syphilis Latent Syphilis Tertiary Syphilis Neurosyphilis Asymptomatic Neurosyphilis Syphilitic Meningitis Meningovascular Syphilis Parenchymatous Syndromes Central Nervous System Gumma Ocular Syphilis Otosyphilis Cardiovascular Syphilis Late Benign (Gummatous) Syphilis Laboratory Diagnosis Direct Examination for Spirochetes Darkfield Microscopy and Direct Fluorescent Antibody Test for Treponema pallidum Visualization of Treponema pallidum in Tissues Polymerase Chain Reaction Detection of Treponema pallidum Serologic Tests Nontreponemal Tests Treponemal Tests Syphilis Serologic Tests in HIV Infection Rapid Point-of-Care Tests Tests for Neurosyphilis Therapy Principles of Syphilotherapy Incubating or Early Syphilis Latency Tertiary Syphilis Cardiovascular and Gummatous Syphilis Neurosyphilis Penicillin Allergy Gestational Syphilis Jarisch-Herxheimer Reaction Response to Therapy Congenital Syphilis Immunity Acknowledgments Key References References 238 Endemic Treponematoses Short View Summary Microbiology Morphology Antibiotic Sensitivity Epidemiology Transmission Clinical Manifestations Late Complications and Sequelae Differential Diagnosis Yaws Endemic Syphilis (Bejel) Pinta Attenuated Disease Diagnosis Direct Visualization Serology Point-of-Care Syphilis and Endemic Treponematosis Test Polymerase Chain Reaction Therapy Prevention Key References References 239 Leptospira Species (Leptospirosis) Short View Summary History Etiology Epidemiology and Transmission Pathogenesis Clinical Manifestations Laboratory Diagnosis Direct Detection Methods Isolation and Identification Indirect Detection Methods Therapy Prevention Key References References 240 Relapsing Fever Caused by Borrelia Species Short View Summary Organism Epidemiology and Transmission Pathophysiology Clinical Manifestations Diagnosis Therapy Prevention Borrelia miyamotoi Key References References 241 Lyme Disease (Lyme Borreliosis) Due to Borrelia burgdorferi Short View Summary Causative Organism Vector of Transmission and Animal Hosts Epidemiology Pathogenesis Clinical Characteristics Early Infection: Stage 1 (Localized Infection) Early Infection: Stage 2 (Disseminated Infection) Late Infection: Stage 3 (Persistent Infection) Post–Lyme Disease Symptoms or Syndrome Congenital Infection Coinfection Laboratory Diagnosis Differential Diagnosis Therapy Prevention Key References References vi. Anaerobic Bacteria 242 Anaerobic Infections Short View Summary Definition of an Anaerobe Anaerobes in the Normal Human Microbiota The Microbiome in Health and Disease Etiology and Microbiology of Anaerobic Clinical Infections Anaerobic Gram-Negative Bacilli Anaerobic Gram-Positive Cocci Anaerobic Gram-Positive Non–Spore-Forming Rods Anaerobic Spore-Forming Bacilli Clinical Syndromes Caused by Anaerobes Anaerobic Infections of the Mouth, Head, and Neck Central Nervous System Infections Pleuropulmonary Infections Intraabdominal Infections Female Genital Tract Infections Skin and Soft Tissue Infections Bone and Joint Infections Anaerobic Bacteremia Pathogenesis of Anaerobic Infections Diagnosis of Anaerobic Infections Treatment of Anaerobic Infections and Antibiotic Resistance Acknowledgment Key References References 243 Clostridioides difficile (Formerly Clostridium difficile) Infection Short View Summary Historical Overview Pathogenesis The Indigenous Gut Microbiota and Antibiotics Sporulation and Germination in Clostridioides difficile Toxin Production Other Virulence Factors Host Response to Clostridioides difficile Infection Pathogenesis of Recurrent Clostridioides difficile Infection Altered Virulence in Specific Clostridioides difficile Lineages Epidemiology Health Care–Associated Clostridioides difficile Infection Community-Associated Clostridioides difficile Infection Molecular Epidemiology of Clostridioides difficile Infection and Importance of Strain Type Clostridioides difficile Infection in Children Risk Factors Risk for Clostridioides difficile Infection Risk for Recurrent Clostridioides difficile Infection Risk for Severe Clostridioides difficile Infection Infection Control and Prevention Clinical and Pathologic Manifestations Diagnosis Treatment Mild-to-Moderate Clostridioides difficile Infection Severe Clostridioides difficile Infection Severe Complicated or Fulminant Clostridioides difficile Infection First Recurrence of Clostridioides difficile Infection Multiple Recurrences of Clostridioides difficile Infection and Fecal Microbiota Transplantation Monitoring Outcome of Treatment Conclusions Key References References 244 Tetanus (Clostridium tetani) Short View Summary History Epidemiology Causes of Tetanus Mortality Microbiology of Clostridium Tetani Pathogenesis Clinical Manifestations Diagnosis Treatment Stabilization Management of Muscle Spasms Wound Management Passive Immunization Antimicrobial Therapy Management of Autonomic Dysfunction Nutritional Support Prevention Key References References 245 Botulism (Clostridium botulinum) Short View Summary History of Botulism Epidemiology Microbiology of Clostridium Botulinum Pathogenesis Clinical Manifestations Diagnosis Therapy Prevention Key References References 246 Diseases Caused by Clostridium Short View Summary Characteristics of Clostridium Species Microbiology Pathogenesis Major Infections and Intoxications Clostridioides difficile Infection Historical Perspective Clinical Manifestations Molecular Pathogenesis Treatment and Diagnosis CDI: an Emerging Public Health Crisis Clostridium perfringens and Clostridial Myonecrosis (Gas Gangrene) Pathogenesis Diagnosis and Treatment Clostridium botulinum and Botulism Clostridium tetani and Tetanus Food Poisoning Caused by Clostridium Species Other Clostridial Infections Bacteremia Abdominal Infections Biliary Tract Infections Female Genital Tract Infections Pleuropulmonary Infections Key References References 247 Bacteroides, Prevotella, Porphyromonas, and Fusobacterium Species (and Other Medically Important Anaerobic Gram-Negative Bacilli) Short View Summary Overview History Microbiology Bacteroides Prevotella and Porphyromonas Fusobacterium Symbiosis Gastrointestinal Tract Symbiosis and Mutualism in Immunity and Metabolism Female Urogenital Tract Oropharynx Opportunism Endotoxic Lipopolysaccharide Capsular Polysaccharides Pili and Fimbriae Enzymes and Toxins Metabolic End Products Host Immune Response Infections Bacteremia Skeletal Infection Skin and Soft Tissue Infection Central Nervous System Infection Infections of the Aerodigestive Tract Oropharyngeal Infections Salivary Gland Infections Ear Infections Thoracic Infections Cardiovascular Infections Intraabdominal Infections Peritonitis Enteritis Urogenital Tract Infections Recent Associations of Gram-Negative Anaerobic Rods and Disease Therapy Surgical Treatment Antibiotic Therapy Key References References 248 Anaerobic Cocci and Anaerobic Gram-Positive Nonsporulating Bacilli Short View Summary Taxonomy Members of the Commensal Microbiota Clinical Significance Gram-Positive Anaerobic Cocci Anaerococcus Finegoldia Parvimonas Peptoniphilus Peptostreptococcus Murdochiella Ruminococcus Gram-Negative Anaerobic Cocci Acidaminococcus Anaeroglobus Megasphaera Negativicoccus Veillonella Gram-Positive Anaerobic Nonsporulating Rods Propionibacteria Lactobacilli Bifidobacteria Atopobium and Olsenella Actinomyces-Like Organisms Mobiluncus Eggerthella and Related Species Eubacterium and Related Taxa Microbiologic Aspects Treatment Key References References vii. Mycobacterial Diseases 249 Mycobacterium tuberculosis Short View Summary History Microbiology Acid-Fast Staining Culture Methods for Mycobacterium tuberculosis Nucleic Acid Amplification Detection of Mycobacterial Antigens in Urine Speciation of Mycobacteria Genotyping of Mycobacterium tuberculosis Drug Susceptibility Testing Epidemiology General Considerations Recent Morbidity and Mortality Trends Drug-Resistant Tuberculosis Mode of Spread Risk for Infection Influence of Chemotherapy on Spread of Infection Risk for Progression From Infection to Active Disease Institutional Spread of Tuberculosis Hospitals Shelters for the Homeless Correctional Facilities Controlling Nosocomial Spread Immunology Testing for Latent Tuberculosis Infection Tuberculin Skin Test Dosage Technical Aspects Targeted Tuberculin Testing Interpretation Booster Effect False-Positive and False-Negative Reactions Variant (“Delayed”) Tuberculin Reactivity Loss of Tuberculin Reactivity Tuberculin Skin Testing and HIV Infection Interferon-γ Release Assays for Latent M. tuberculosis Infection Pathogenesis Evolution of the Primary Infection Primary (Childhood) and Reinfection (Adult) Tuberculosis Chronic Pulmonary Tuberculosis Apical Localization Endogenous Versus Exogenous Reinfection Influence of Age on Tuberculous Infection Infection in Infancy and Childhood Infection in Adolescence and Young Adulthood Infection in Midadulthood Infection in Old Age Late Hematogenous Tuberculosis Intercurrent Events Tuberculosis in People With HIV Infection Pulmonary Tuberculosis Primary Tuberculosis in Childhood Postprimary (Adult-Type) Pulmonary Tuberculosis Lower Lobe and Endobronchial Tuberculosis Progressive Lower Lobe Disease in Older Persons Endobronchial Tuberculosis Pulmonary Tuberculosis in AIDS Tuberculomas Symptoms Physical Examination Radiographic Findings Laboratory Findings Diagnosis Fiberoptic Bronchoscopy Tuberculosis Diagnosed at Autopsy Tuberculosis and Cancer Therapy Antituberculous Drugs Isoniazid Rifampin Rifapentine Pyrazinamide Ethambutol Streptomycin Fluoroquinolones Bedaquiline Second-Line Agents Third-Line Agents Agents Under Development Selecting a Drug Regimen Standard Regimens Based on Isoniazid and Rifampin Directly Observed Treatment Regimens of Less Than 6 Months for Minimal Disease Fixed-Dose Combination Tablets Treatment of Multidrug-Resistant Tuberculosis Therapy for Extensively Drug-Resistant Tuberculosis Course of Therapy and Duration of Observation Retreatment Other Forms of Treatment Corticosteroids Treatment of Tuberculosis in HIV-Infected Patients Immune Reconstitution Inflammatory Syndrome Duration of Therapy Other Special Treatment Circumstances Childhood Pregnancy Uremia and End-Stage Renal Disease Liver Disease Patients Receiving Immunosuppressive Drugs Treatment of Latent Tuberculous Infection Drug Regimens Risk for Isoniazid Hepatotoxicity During Treatment of Latent Tuberculous Infection Treatment of Contacts of Active Cases Treatment of Quiescent, Previously Untreated Pulmonary Tuberculosis Treatment of Individuals With Recent Infection Treating Latent Tuberculous Infection in Persons With HIV Infection Mycobacterium tuberculosis Infection in Persons With Additional Risk Factors Pregnant Women The Nursing Home Problem Vaccination Extrapulmonary Tuberculosis AIDS and Extrapulmonary Tuberculosis General Comments on Treatment of Extrapulmonary Tuberculosis Miliary Tuberculosis Usual (Acute) Miliary Tuberculosis Cryptic Miliary Tuberculosis and Late Generalized (Chronic Hematogenous) Tuberculosis Nonreactive Tuberculosis Miliary Tuberculosis and Hematologic Abnormalities Primary Hepatic Tuberculosis Miliary Tuberculosis in AIDS Central Nervous System Tuberculosis: Tuberculous Meningitis Pathologic Features Clinical Manifestations Therapy Tuberculomas Tuberculous Spinal Meningitis Tuberculous Pleurisy (Serofibrinous Pleurisy With Effusion) Types of Tuberculous Pleurisy Early Postprimary Pleurisy With Effusion Pleurisy With Effusion Complicating Chronic Pulmonary Tuberculosis Pleurisy With Effusion Complicating Miliary Tuberculosis Clinical Manifestations and Diagnosis Therapy Tuberculous Empyema and Bronchopleural Fistula Tuberculous Pericarditis Clinical Manifestations and Diagnosis Therapy Skeletal Tuberculosis: Pott Disease (Tuberculous Spondylitis) Clinical Manifestations Abscess and Sinus Formation Spinal Tuberculosis Without Bony Involvement on Plain Films Pott Paraplegia Therapy Peripheral Osteoarticular Tuberculosis Genitourinary Tuberculosis: Renal Tuberculosis Male Genital Tuberculosis Genitourinary Tuberculosis in AIDS Female Genital Tuberculosis Gastrointestinal Tuberculosis Gastrointestinal Tuberculosis in AIDS Tuberculous Peritonitis Tuberculous Lymphadenitis (Scrofula): Peripheral Nodes Mediastinal Tuberculous Lymphadenopathy Fibrosing Mediastinitis Mesenteric Tuberculous Lymphadenitis Cutaneous Tuberculosis Tuberculous Laryngitis Tuberculous Otitis Miscellaneous Conditions Mycobacterium bovis and Bacillus Calmette-Guérin Key References References 250 Leprosy (Mycobacterium leprae) Short View Summary History and Society Epidemiology Genetic Epidemiology Zoonotic Potential Nosocomial Infections Global Epidemiology Epidemiology in the United States Microbiology Mechanisms of Immunity Clinical Manifestations of Leprosy Clinical Presentation Diagnostic Testing Treatment of Leprosy Antibiotics Drug Resistance Surgical Intervention Physical Therapy and Occupational Therapy Interventions Monitoring Treatment Response Prevention of Leprosy Pathologic Immune Reactions of Leprosy Type 1 Reversal Reaction Neuritis Type 2 Erythema Nodosum Leprosum Necrotic Vasculitis (Lucio Phenomenon) Considerations for People With Altered Immunity Key References References 251 Mycobacterium avium Complex Short View Summary Epidemiology Reservoir and Route of Acquisition Pulmonary Disease Extrapulmonary Disease Pathogen: Classification and Microbiology Organisms Virulence Pathogenesis Pulmonary Disease Extrapulmonary Disease Host Immunity Pulmonary Disease Extrapulmonary Disease Clinical Manifestations Pulmonary Disease Extrapulmonary Disease Diagnosis Pulmonary Disease Extrapulmonary Disease Treatment and Prevention Principles of Treatment Specific Antimicrobials Antimicrobial Tolerability Drug Interactions Drug Dosing in Impaired Renal Function Serum Drug Level Monitoring Macrolide-Resistant Mycobacterium avium Complex Disease Immunomodulatory Treatment of Mycobacterium avium Complex Disease Specific Organ System Treatment Considerations Pulmonary Mycobacterium avium Complex Treatment Choice and Monitoring Surgery Hypersensitivity Pneumonitis Extrapulmonary Disease Disseminated Disease Prevention. Other Localized Disease Key References References 252 Infections Caused by Nontuberculous Mycobacteria Other Than Mycobacterium avium Complex Short View Summary Overview Rapidly Growing Mycobacteria Slowly Growing Mycobacteria Intermediately Growing Mycobacteria Nontuberculous Mycobacteria and the Environment Nontuberculous Mycobacteria and Clinical Disease Pulmonary Disease Geography of Common Nontuberculous Mycobacteria Species Nontuberculous Mycobacteria Species Associated Infrequently With Pulmonary Disease Pulmonary Syndromes Associated With Nontuberculous Mycobacteria Other Than Mycobacterium avium Complex Clinical Presentation of Nontuberculous Mycobacterial Lung Disease Treatment of Mycobacterium avium Complex Lung Disease Treatment of Mycobacterium kansasii Lung Disease Treatment of Mycobacterium abscessus subsp. abscessus and Mycobacterium abscessus subsp. massiliense Lung Disease Treatment of Other Nontuberculous Mycobacterial Lung Disease Lymphadenitis Localized Cutaneous, Joint, and Soft Tissue Infections Intermediately Growing Mycobacteria Mycobacterium marinum Community-Acquired Extrapulmonary Infections Due to Rapidly Growing Mycobacteria Slowly Growing Mycobacteria Health Care–Associated Infections Skin/Soft Tissue Diagnosis and Treatment Infection of Tendon Sheaths, Bones, Bursae, and Joints Disseminated Disease Catheter-Related Infections Miscellaneous Infections Laboratory Aspects Stain and Culture Identification Susceptibility Testing: Rapidly Growing Mycobacteria Susceptibility Testing: Slowly Growing Nontuberculous Mycobacteria Strain Comparison Key References References viii Higher Bacterial Diseases 253 Nocardia Species Short View Summary Classification Molecular Identification and Taxonomy Ecology and Epidemiology Pathology Pathogenesis Immune Response to Nocardia Infection Specific Virulence Determinants Host Cell–Nocardia Interactions Biofilms Clinical Epidemiology Nocardia Species and Disease Associations Immunocompromise as a Risk Factor for Nocardiosis Chronic Lung Disease as a Risk Factor for Nocardiosis Clinical Manifestations Primary Cutaneous Nocardiosis Pulmonary Disease Radiologic Manifestations of Pulmonary Nocardiosis Differential Diagnosis of Pulmonary Nocardiosis Central Nervous System Nocardiosis Disseminated Nocardiosis Keratitis Colonization Laboratory Diagnosis Identification of Nocardia Species Management Antimicrobial Selection In Vitro Susceptibility Testing Antimicrobial Regimens Trimethoprim-Sulfamethoxazole Other Regimens Amikacin and Carbapenems Third-Generation Cephalosporins Oxazolidinones: Linezolid and Tedizolid Minocycline and Amoxicillin-Clavulanate Fluoroquinolones, Macrolides, and Tigecycline Superficial Infection and Mycetoma Nocardia Intravascular Catheter-Related Bloodstream Infection Severe Infection Empirical Therapy Surgical Management Surgery in Extraneural Nocardiosis Surgery in Cerebral Nocardiosis Keratitis and Other Eye Infections Keratitis Endophthalmitis Duration of Therapy and Prognosis Clinical Responses to Therapy Causes of Therapeutic Failure Management of Immunosuppressive Drug Therapy in Patients With Nocardiosis Duration of Therapy in Immunocompetent Hosts Duration of Therapy in Immunosuppressed Hosts Short-Course Therapy Prophylaxis Primary Prophylaxis Secondary Prophylaxis Clinical Outcomes Effect of Nocardia Species on Outcome Summary of Management Key References References 254 Agents of Actinomycosis Short View Summary Etiologic Agents Epidemiology Pathogenesis and Pathology Clinical Manifestations Oral-Cervicofacial Disease Thoracic Disease Endocarditis, Pericarditis, and Mediastinal Disease Abdominal Disease Pelvic Disease Central Nervous System Disease Musculoskeletal Disease Disseminated Disease Diagnosis Therapy Key References References G Mycoses 255 Introduction to Mycoses Changes in How Fungi Are Identified Identification by DNA Sequence Cryptic Species One Fungus, One Name Common Features of Pathogenic Fungi Yeasts and Molds Dimorphic Fungi Diagnosis of Mycoses Microscopic Appearance of Fungi Tissue Stains Fresh Clinical Specimens Serologic Diagnosis Epidemiology References 256 Candida Species Short View Summary Pathogen Epidemiology and Ecology Pathogenesis and Immunology Clinical Manifestations Mucous Membrane Infections Thrush Candida Esophagitis Nonesophageal, Mucous Membrane, Gastrointestinal Candidiasis Candida Vaginitis Cutaneous Candidiasis Syndromes Generalized Cutaneous Candidiasis Erosio Interdigitalis Blastomycetica Candida Folliculitis Candida Balanitis Cutaneous Lesions of Disseminated Candidiasis Intertrigo Paronychia and Onychomycosis Diaper Rash Perianal Candidiasis Chronic Mucocutaneous Candidiasis Deep Organ Involvement Central Nervous System Candidiasis Respiratory Tract Candidiasis Cardiac Candidiasis Candida Endocarditis Urinary Tract Candidiasis Candida Arthritis, Osteomyelitis, Costochondritis, and Myositis Intraabdominal Candidiasis: Candida Infection of Peritoneum, Liver, Spleen, and Gallbladder Candidemia Ocular Candidiasis Endogenous Ocular Candidiasis Exogenous Ocular Candidiasis “Chronic Candidiasis Syndrome” or “the Yeast Connection” Treatment and Prophylaxis General Comments Systemic Drugs for Candidiasis Polyenes Triazoles Echinocandins Flucytosine Candidemia in Nonneutropenic Patients Candidemia in Neutropenic Patients Candida Infections of the Cardiovascular System Central Nervous System Candida Infection Intraabdominal Candidiasis, Candida Peritonitis, Gallbladder Infection Urinary Candidiasis Mucocutaneous Candidiasis Chronic Mucocutaneous Candidiasis Ocular Candidiasis Key References References 257 Aspergillus Species Short View Summary Mycology Epidemiology Pathogenicity and Host Defenses Clinical Presentation Allergic Manifestations of Disease Allergic Bronchopulmonary Aspergillosis Other Allergic Manifestations Saprophytic Colonization and Superficial Aspergillosis Fungus Balls Due to Aspergillus Other Superficial or Colonizing Syndromes of Aspergillosis Invasive Syndromes Caused by Aspergillus Invasive Pulmonary Aspergillosis Tracheobronchitis Sinusitis Disseminated Infection Other Invasive Syndromes Cerebral Aspergillosis Bone Aspergillosis Cutaneous Infection Other Sites Diagnosis and Antifungal Resistance Therapy (Table 257.4) Primary Antifungal Therapy Voriconazole Alternative Primary Therapy Isavuconazole Lipid Amphotericin Formulations Other Antifungal Agents Amphotericin B Deoxycholate Other Polyenes Other Triazoles Echinocandins Combination Antifungal Therapy Adjuvant Therapy Approach to Therapy Prevention and Prophylaxis Key References References 258 Agents of Mucormycosis and Entomophthoramycosis Short View Summary Etiology Insights From Genomic Sequencing Acquisition of Infection Patient Populations at Risk Incidence of Mucormycosis Pathogenesis (Fig. 258.3) Role of Iron Uptake in Mucormycosis Pathogenesis Host Immune Response Against Mucormycosis Histopathology Clinical Manifestations of Mucormycosis Rhinocerebral Infections Clinical Presentation Radiology Pulmonary Infections Clinical Presentation Radiology Pulmonary Mucormycosis in Less Severely Immunocompromised Patients Skin and Soft Tissue Infections Osteomyelitis Gastrointestinal Mucormycosis Disseminated Mucormycosis Less Common Presentations of Mucormycosis Diagnosis Species Identification Differentiating Mucormycosis From Other Molds Antifungal Susceptibility Testing Combination Therapy Treatment Antifungal Therapy Lipid Amphotericin B Formulations Triazoles Combination Therapy Treatment Duration Prophylaxis Surgical Management Adjunctive Therapies Prognosis Entomophthoramycosis Conidiobolomycosis Basidiobolomycosis Diagnosis Differential Diagnosis Therapy and Prevention Key References References 259 Sporothrix schenckii Short View Summary Mycology Epidemiology Clinical Syndromes Lymphocutaneous Sporotrichosis Extracutaneous Sporotrichosis Multifocal Extracutaneous Sporotrichosis Clinical Manifestations of Sporotrichosis in the HIV-Infected Patient Diagnosis Therapy Therapy of Patients With Acquired Immunodeficiency Syndrome Itraconazole Blood Level Monitoring Prognosis Key References References 260 Agents of Chromoblastomycosis Short View Summary Etiologic Agents Epidemiology Pathology and Pathogenesis Clinical Manifestations Diagnosis Therapy Key References References 261 Agents of Mycetoma Short View Summary Etiologic Agents Epidemiology Pathology and Pathogenesis Clinical Manifestations Diagnosis Therapy Prevention Key References References 262 Cryptococcosis (Cryptococcus neoformans and Cryptococcus gattii) Short View Summary History Mycology Life Cycle and Genetics Taxonomy Identification Ecology Cryptococcus neoformans Serotypes A, D, and AD (grubii var. or neoformans var.) Cryptococcus gattii Serotypes B and C Epidemiology Pathogenicity Capsule Melanin High-Temperature Growth Other Pathogenicity Factors Host Responses Pathogenesis Clinical Manifestations Lung Central Nervous System Skin Prostate Eye Other Body Sites Immune Reconstitution Inflammatory Syndrome Laboratory Diagnosis Microscopic Examination Cultures Antigen Detection Radiology Management In Vitro Drug Susceptibility Analysis Treatment Strategies Cryptococcal Meningitis Prognosis Prevention Key References References 263 Histoplasma capsulatum (Histoplasmosis) Short View Summary History Ecology and Epidemiology Mycology Pathogenesis Innate Immunity Adaptive Immunity Genetic Predisposition to Disease Granulomas Delayed-Type Hypersensitivity Pulmonary Histoplasmosis Acute Infections Acute Primary Infection Symptoms Clinical Findings Pericarditis Differential Diagnosis Acute Reinfection Complications of Primary Histoplasmosis Histoplasmoma Mediastinal Granuloma and Fibrosis Chronic Pulmonary Histoplasmosis Symptoms Laboratory Findings Pathology Noncavitary Chronic Pulmonary Disease Progressive Disseminated Histoplasmosis Incidence Reactivation Versus New Exposure Pathology Acute Progressive Disseminated Histoplasmosis Laboratory Abnormalities Progressive Disseminated Histoplasmosis and HIV Laboratory Abnormalities in Coinfection Subacute Progressive Disseminated Histoplasmosis Clinical Features Endovascular Infection Central Nervous System Involvement Chronic Progressive Disseminated Histoplasmosis Clinical Findings Ocular Histoplasmosis African Histoplasmosis Diagnosis Fungal Culture Antigen Detection Serology Histochemical Identification Miscellaneous Laboratory Tests Therapy Acute Pulmonary Histoplasmosis Mediastinal Granuloma, Mediastinal Fibrosis, and Histoplasmoma Cavitary Pulmonary Histoplasmosis Acute Progressive Disseminated Histoplasmosis Subacute and Chronic Progressive Disseminated Histoplasmosis Meningitis Endocarditis Pericarditis Arthropathies Presumed Ocular Histoplasmosis Other Considerations Immune Reconstitution Syndrome and Histoplasma Prevention Prophylaxis of Immunocompromised Persons Other Considerations Key References References 264 Blastomycosis Short View Summary History Mycology Geographic Distribution and Ecology Epidemiology Pathogenesis, Virulence, and Host Defense Clinical Manifestations Pulmonary Blastomycosis Disseminated Blastomycosis Blastomycosis in Immunocompromised Patients Pregnancy Diagnosis Treatment Acknowledgment Key References References 265 Coccidioidomycosis (Coccidioides Species) Short View Summary Mycology Mycelial (Saprobic) Growth Spherule (Parasitic) Growth Epidemiology Geographic Range Rates of Coccidioidal Infection Pathogenesis and Control Histopathology Host Defenses Clinical Manifestations Early Respiratory Infection Pulmonary Nodules and Cavities Chronic Fibrocavitary Pneumonia Extrapulmonary Dissemination Diagnosis Direct Examination and Culture Serologic Testing Tube Precipitin Antibodies Complement-Fixing Antibodies Immunodiffusion Tests Enzyme-Linked Immunoassays Latex Tests Skin Testing Coccidioidal Antigen Detection Management General Approaches Therapy Early Uncomplicated Infections Diffuse Pneumonia Pulmonary Cavity Chronic Fibrocavitary Pneumonia Extrapulmonary Dissemination New Therapies Prevention Key References References 266 Dermatophytosis (Ringworm) and Other Superficial Mycoses Short View Summary Dermatophytosis Dermatophytes Epidemiology Zoophilic Dermatophyte Infections Geophilic Dermatophyte Infections Anthropophilic Dermatophyte Infections Age Incidence Pathogenesis Clinical Manifestations Tinea Pedis Tinea Cruris Tinea Corporis Tinea Imbricata Tinea Manuum Tinea Faciei Tinea Capitis Onychomycosis Caused by Dermatophytes Deep Dermatophyte Infections Dermatophyte “Id” Reactions Point of Care and Laboratory Diagnosis Therapy Ringworm of the Glabrous Skin (Tinea Pedis, Corporis, Manuum) Topical Therapy Systemic Therapy Tina Capitis Onychomycosis Neoscytalidium Infections Clinical Manifestations Diagnosis Therapy Other Forms of Onychomycosis Pityriasis Versicolor Organisms Pathogenesis Clinical Manifestations Therapy Other Malassezia Infections Malassezia Folliculitis Seborrheic Dermatitis Clinical Manifestations Therapy Tinea Nigra White Piedra Black Piedra Key References References 267 Paracoccidioidomycosis Short View Summary Description of the Pathogen Ecology and Epidemiology Pathogenesis and the Immune Response Innate Immune Responses Acquired Immune Responses Humoral Immune Responses Immunoregulation, Immunomodulation, and Vaccines Clinical Manifestations Characteristics of the Lesions Lungs Mucosa Skin Lymph Nodes Adrenal Glands Other Lesions Paracoccidioidomycosis in Human Immunodeficiency Virus–Infected Patients Paracoccidioidomycosis and Cancer Differential Diagnosis Treatment Sulfonamides Amphotericin B Azole Derivatives Immune Stimulation Criteria of Recovery Laboratory Diagnosis Direct Examination Histopathology Cultures Immune-Based Diagnostic Tests Molecular Testing Skin Tests Key References References 268 Uncommon Fungi and Related Species Short View Summary Scedosporium Apiospermum (Pseudallescheria Boydii) Species Complex Lomentospora (Formerly Scedosporium) Prolificans Dark-Walled Fungi and Agents of Phaeohyphomycosis Fusarium Spp. Other Opportunistic Molds Trichosporon Spp. Malassezia Furfur Other Uncommon Yeasts Talaromyces (Formerly Penicillium) Marneffei Lacazia Loboi Agents of Adiaspiromycosis (Emmonsia Spp.) Emergomyces Africanus and Other Emergomyces Species Prototheca Spp. Pythium Spp. Rhinosporidium Seeberi Summary Key References References 269 Pneumocystis Species Short View Summary Pathogen Epidemiology Pathology and Pathogenesis Clinical Manifestations Other Clinical Manifestations Diagnosis Granulomatous Pneumocystosis Course and Prognosis Treatment Prevention Chemoprophylaxis Stopping Prophylaxis Prophylaxis of PCP Among Patients With Non–HIV-Associated Immunosuppression Boosting Host Immune Response Preventing Exposure Key References References 270 Microsporidiosis Short View Summary General Characteristics Phylogeny of the Microsporidia Epidemiology Immunology Pathology and Pathogenesis Gastrointestinal Tract Infections Genitourinary Tract Infection Central Nervous System Infection Ocular Infection Musculoskeletal Infection Sinus and Respiratory Infection Skin Clinical Manifestations Microsporidian Infection in Non-AIDS Patients Microsporidian Infection in AIDS Patients Enterocytozoonidae Encephalitozoonidae Other Microsporidia Diagnosis Therapy Gastrointestinal and Systemic Disease Ocular Disease Prevention Key References References H Protozoal Diseases 271 Introduction to Protozoal Diseases Key References References 272 Entamoeba Species, Including Amebic Colitis and Liver Abscess Short View Summary Organism Species of Entamoeba Genotypes of Entamoeba histolytica Life Cycle Metabolism Cell Biology Genome Structure Pathogenesis Adherence Cytolysis Phagocytosis Role of Bacteria Cysteine Proteinases Role of Leptin in Host Resistance Macrophage Migration Inhibitory Factor and Inflammation Immune Response and Immunity Innate Immunity Neutrophils and Eosinophils Macrophages Natural Killer Cells and Natural Killer T Cells Activated Mast Cells Complement-Mediated Lysis of Entamoeba histolytica Intestinal Epithelial Cells Acquired Immunity Mucosal Immunoglobulin A Response Cell-Mediated Response Epidemiology Clinical Manifestations Asymptomatic Intraluminal Amebiasis Amebic Diarrhea Amebic Dysentery or Colitis Amebic Liver Abscess Metastatic Amebiasis Diagnosis Stool Ova and Parasite Examination Culture Antigen Testing for Amebiasis Polymerase Chain Reaction Testing for Amebiasis Serologic Tests for Amebiasis Colonoscopy and Biopsy Imaging Therapy Noninvasive Infections Invasive Infections Prevention Key References References 273 Free-Living Amebae Short View Summary Organisms Naegleria Acanthamoeba Balamuthia Other Free-Living Amebae Reported in Human Disease Epidemiology Naegleria Acanthamoeba Balamuthia Pathogenesis and Pathologic Findings Naegleria Acanthamoeba Balamuthia Clinical Manifestations Naegleria Acanthamoeba Balamuthia Laboratory Diagnosis Naegleria Acanthamoeba Balamuthia Treatment Naegleria Clinical Evidence Animal Models and In Vitro Assays Recommendations Acanthamoeba Granulomatous Amebic Encephalitis and Disseminated Disease Clinical Evidence Animal Models and In Vitro Assays Recommendations Acanthamoeba Keratitis Recommendations Balamuthia Clinical Evidence In Vitro Assays Recommendations Prevention Resources Key References References 274 Malaria (Plasmodium Species) Short View Summary The Malaria Problem Plasmodium and Its Life Cycle Pathophysiology The Malaria Paroxysm and General Considerations Plasmodium falciparum Cerebral Malaria Hypoglycemia Anemia Pulmonary Edema and Respiratory Distress Metabolic (Lactic) Acidosis Malaria of Pregnancy Plasmodium vivax and Plasmodium ovale Plasmodium malariae Plasmodium knowlesi Genetic Resistance to Malaria Hemoglobins S, C, and E Thalassemias Hemoglobin F Glucose-6-Phosphate Dehydrogenase Deficiency Southeast Asian Ovalocytosis and Hereditary Xerocytosis ABO Blood Groups Duffy Antigen Receptor for Chemokines Negativity Acquired Immunity and Antigenic Variation Epidemiology of Malaria Distribution of Drug Resistance Antimalarial Drugs: Mechanisms of Action and Resistance Chloroquine Amodiaquine Piperaquine Sulfadoxine-Pyrimethamine Atovaquone-Proguanil (Malarone) Doxycycline Mefloquine, Quinidine, Quinine Artemisinin Derivatives Clinical Presentation and Diagnosis of Malaria History and Physical Examination Thick and Thin Blood Smears Rapid Diagnostic Tests Other Laboratory Tests Severe P. falciparum Malaria Distinguishing Malaria From Other Illnesses With Similar Clinical Presentations Influenza Enteric Fever Bacteremia/Sepsis Dengue Fever Acute Schistosomiasis (Katayama Fever) Leptospirosis African Tick Fever East African Trypanosomiasis (Sleeping Sickness) Yellow Fever Therapy (see also Chapter 41) General Principles Uncomplicated Malaria Chloroquine Phosphate Atovaquone-Proguanil (Malarone) Artemisinin-Based Combination Therapies Quinine Plus Doxycycline Mefloquine Standby Emergency Treatment of Uncomplicated Malaria in Travelers Intermittent Presumptive Treatment in Infants, Children, and Pregnant Women Seasonal Malaria Chemoprevention Mass Drug Administration Severe Malaria Quinidine Gluconate Artemisinin and Its Derivatives Quinine Dihydrochloride Bacteremia and Sepsis in Severe Malaria Exchange Transfusion in Severe Malaria Nonfalciparum Malaria Prevention Risk Assessment Chemoprophylaxis Areas With Chloroquine-Sensitive Malaria Areas With Mefloquine-Sensitive Malaria All Areas Mosquito Repellent and Avoidance Measures Vaccination Key References References 275 Leishmania Species Short View Summary Overview and General Principles Life Cycle and Morphology Taxonomy and Classification Transmission Principles and Sand Fly Biology Pathogenesis and Immunology Diagnostic Principles Treatment Principles Visceral Leishmaniasis Epidemiology Pathogenesis and Immunology Natural History and Latent Visceral Leishmaniasis Infection Clinical Manifestations Diagnosis Visceral Leishmaniasis in Immunocompromised Patients Post–Kala-Azar Dermal Leishmaniasis Treatment Liposomal Amphotericin B and Other Formulations Pentavalent Antimony Miltefosine Paromomycin Combination Therapy for Visceral Leishmaniasis Treatment and Secondary Prophylaxis of Visceral Leishmaniasis in Immunocompromised Hosts Treatment of Post–Kala-Azar Dermal Leishmaniasis Cutaneous Leishmaniasis Epidemiology Pathogenesis and Immunology Clinical Manifestations of New World and Old World Cutaneous Leishmaniasis Diffuse Cutaneous Leishmaniasis Leishmaniasis Recidivans Disseminated Leishmaniasis Diagnosis Treatment Old World Cutaneous Leishmaniasis New World Cutaneous Leishmaniasis Pentavalent Antimony Liposomal Amphotericin B Pentamidine Azoles Miltefosine Mucosal Leishmaniasis Epidemiology Pathogenesis and Immunology Clinical Manifestations Diagnosis Treatment Prevention Key References References 276 Trypanosoma Species (American Trypanosomiasis, Chagas Disease) Short View Summary Chagas Disease Life Cycle and Transmission Pathology Epidemiology Clinical Manifestations Immunosuppression and Transplantation in T. Cruzi–Infected Patients Diagnosis Therapy Prevention Key References References 277 Agents of African Trypanosomiasis (Sleeping Sickness) Short View Summary Parasites and Their Transmission Pathogenesis and Pathology Epidemiology West African Trypanosomiasis East African Trypanosomiasis Clinical Course West African Trypanosomiasis East African Trypanosomiasis Diagnosis Therapy Prevention Key References References 278 Toxoplasma gondii Short View Summary Etiology Organism Stages Oocyst Tachyzoite Tissue Cyst Transmission and Epidemiology Pathogenesis and Immunity Genetic Susceptibility Pathology Lymph Node Central Nervous System Lung Eye Skeletal and Heart Muscle Other Organ Systems Clinical Manifestations Toxoplasmosis in the Immunocompetent Patient Toxoplasmosis in the Immunodeficient Patient Toxoplasmosis in the Solid-Organ Transplant Patient Heart Transplantation Kidney Transplantation Liver Transplantation Toxoplasmosis in the Bone Marrow Transplant and Hematopoietic Stem Cell Transplant Recipient Toxoplasmosis in the AIDS Patient Ocular Toxoplasmosis in Immunocompetent Patients Toxoplasmosis During Pregnancy Congenital Toxoplasmosis Diagnosis Serologic Tests for Demonstration of Antibody Immunoglobulin G Antibodies Sabin-Feldman Dye Test Indirect Fluorescent Antibody Test Agglutination and AC/HS Tests Immunoglobulin G Enzyme-Linked Immunosorbent Assay Immunoglobulin G Avidity Test Immunoglobulin M Antibodies Immunoglobulin M Indirect Fluorescent Antibody Test Immunoglobulin M Enzyme-Linked Immunosorbent Assay Immunoglobulin M Immunosorbent Agglutination Assay Immunoglobulin A Antibodies Immunoglobulin E Antibodies Polymerase Chain Reaction Histologic Diagnosis Isolation of Toxoplasma gondii Radiologic Methods Cerebrospinal Fluid Abnormalities Diagnosis of Specific Clinical Entities Toxoplasmosis in the Immunocompetent Patient Toxoplasmosis in the Immunodeficient Patient Ocular Toxoplasmosis Toxoplasma gondii Infection in Pregnancy Congenital Infection in the Fetus and Newborn Therapy Therapy Regimens in Specific Clinical Entities Toxoplasmosis in the Immunocompetent Patient Toxoplasmosis in the Immunodeficient Patient Ocular Toxoplasmosis Acute Acquired Toxoplasma Infection in Pregnant Women Congenital Infection Prevention and Prophylaxis General Methods Serologic Screening and Prophylaxis Acute Toxoplasma gondii Infection and Toxoplasmosis in the Immunodeficient Patient Congenital Toxoplasma gondii Infection and Toxoplasmosis Acknowledgments Key References References 279 Giardia lamblia Short View Summary Description of the Pathogen Some Unique Biologic Aspects Epidemiology Pathogenesis and Immune Response Clinical Manifestations Diagnosis Therapy Prevention Key References References 280 Trichomonas vaginalis Short View Summary Taxonomy Epidemiology Clinical Manifestations Diagnosis Therapy Complications Key References References 281 Babesia Species Short View Summary Epidemiology United States: Babesia microti Geographic Distribution Incidence and Prevalence Modes of Transmission Tick Bite Blood Transfusion Transplacental Passage Solid Organ Transplantation Risk Factors United States: Other Babesia Species Europe: Babesia divergens Europe: Other Babesia Species Asia: Babesia venatorum Asia: Other Babesia Species Rest of the World Microbiology The Enzootic Cycle of Babesia microti Ticks and Reservoir Hosts Parasite Acquisition by Ticks Parasite Transmission to Hosts Classification of Babesia Species Single-Gene Analysis Whole-Genome Analysis Clinical Manifestations Babesia microti Infection Babesia duncani Infection Babesia divergens Infection Babesia venatorum Infection Pathogenesis Erythrocyte Clearance and Rupture Inflammatory and Immune Response Diagnosis Routine Laboratory Findings Microscopy Nucleic Acid Amplification Serology Therapy Asymptomatic Babesia microti Infection Mild Babesia microti Infection Severe Babesia microti Infection First-Line Antimicrobial Therapy Adjunctive Exchange Transfusion Alternative Antimicrobial Regimens Severely Immunocompromised Patients Asplenic Patients Infection With Other Babesia Species Prevention Acknowledgments Key References References 282 Cryptosporidiosis (Cryptosporidium Species) Short View Summary The Parasites Epidemiology Pathology and Pathogenesis Host Response and Immunity Clinical Manifestations Immunocompetent Individuals in High-Income Countries Childhood Diarrhea in Low- and Middle-Income Countries Cryptosporidium and Malnutrition Cryptosporidiosis in HIV Infection Transplant Patients Diagnosis Management Antiparasitic Drugs Prevention Key References References 283 Cyclospora cayetanensis, Cystoisospora belli, Sarcocystis Species, Balantidium coli, and Blastocystis Species Short View Summary Coccidia Other Than Cryptosporidia Cyclospora Life Cycle Epidemiology Clinical Manifestations Diagnosis Therapy Cystoisospora belli Life Cycle Epidemiology Clinical Manifestations Diagnosis Therapy Sarcocystis Species Life Cycle Epidemiology Clinical Manifestations Diagnosis Therapy Prevention Balantidium coli Life Cycle Epidemiology Clinical Manifestations Diagnosis and Therapy Blastocystis Species Life Cycle Epidemiology Pathogenicity Clinical Manifestations Diagnosis Therapy Acknowledgment Key References References I Diseases Due to Toxic Algae 284 Human Illness Associated With Harmful Algal Blooms Short View Summary Ciguatera Fish Poisoning Paralytic Shellfish Poisoning Neurotoxic Shellfish Poisoning Diarrhetic Shellfish Poisoning Amnesic Shellfish Poisoning Azaspiracid Shellfish Poisoning Cyanobacteria Exposure Syndromes, including Lyngbya Pfiesteria-Associated Syndrome References J Diseases Due to Helminths 285 Introduction to Helminth Infections Biology of Helminths Epidemiology Pathogenesis and Host-Parasite Relationship Diagnosis of Helminth Infections Treatment of Helminth Infections Prevention and Control Key References References 286 Intestinal Nematodes (Roundworms) Short View Summary Intestinal Nematodes Ascaris Lumbricoides Epidemiology Life Cycle Clinical Syndromes Diagnosis Management Enterobius Vermicularis Epidemiology Life Cycle Clinical Syndromes Diagnosis Management Hookworms Epidemiology Life Cycle Clinical Syndromes Diagnosis Management Strongyloides Stercoralis Epidemiology Life Cycle Clinical Syndromes Diagnosis Management Trichuris Trichiura Epidemiology Life Cycle Clinical Syndromes Diagnosis Management Key References References 287 Tissue Nematodes, Including Trichinellosis, Dracunculiasis, Filariasis, Loiasis, and Onchocerciasis Short View Summary Trichinellosis Life Cycle of Trichinella Epidemiology Pathogenesis and Pathology Clinical Manifestations Diagnosis Therapy Prevention Haycocknema Perplexum Infection Dracunculiasis Life Cycle of the Parasite Epidemiology Clinical Manifestations Diagnosis and Therapy Control and Eradication Filariases Lymphatic Filariasis Life Cycle of the Parasite Epidemiology Clinical Manifestations Pathogenesis and Pathology Diagnosis Therapy Prevention, Control, and Eradication Tropical Pulmonary Eosinophilia Loiasis Life Cycle of the Parasite Epidemiology Clinical Manifestations Diagnosis Therapy Prevention and Control Onchocerciasis Life Cycle of the Parasite Epidemiology Pathology and Clinical Manifestations Diagnosis Therapy Prevention and Control Mansonellosis Zoonotic Filariae Reported to Cause Human Disease References 288 Trematodes (Schistosomes and Liver, Intestinal, and Lung Flukes) Short View Summary Schistosomes Life Cycle Epidemiology Pathogenesis Clinical Syndromes Schistosome Dermatitis (“Swimmer’s Itch”) Acute Schistosomiasis (Katayama Fever) Chronic Schistosomiasis Intestinal and Hepatosplenic Schistosomiasis Genitourinary Schistosomiasis Pulmonary Hypertension and Glomerulopathy Ectopic Egg Deposition and Central Nervous System Schistosomiasis Coinfections Diagnosis Parasitologic Tests Serologic Tests Evaluation of Persons With Confirmed Schistosomiasis Therapy Praziquantel for Treatment of Schistosomiasis Other Antischistosomal Drugs: Oxamniquine and Artemisinin Derivatives Management of Acute Schistosomiasis Evaluation of Therapy New Medications for Schistosomiasis Prevention and Control of Schistosomiasis Liver Flukes Clonorchiasis and Opisthorchiasis Clinical Manifestations Diagnosis and Therapy Fascioliasis Clinical Manifestations Diagnosis Therapy Intestinal Flukes Fasciolopsiasis Heterophyiasis, Metagonimiasis, and Haplorchiasis Echinostomiasis Diagnosis and Therapy Lung Flukes Paragonimiasis Clinical Manifestations Diagnosis and Therapy Prevention of Foodborne Fluke Infections Key References References 289 Tapeworms (Cestodes) Short View Summary Cestode Biology Parasite Life Cycle Disease Pathogenesis and Immunology Intestinal Tapeworms Diphyllobothrium latum Hymenolepis nana Taenia saginata Taenia solium Other Species Causing Tapeworm Infection in Humans Diagnosis Therapy Niclosamide Praziquantel Invasive Cestode Infections Cysticercosis Clinical Presentation Diagnosis Treatment Echinococcosis (Hydatid and Alveolar Cyst Disease) Cystic Echinococcosis Clinical Presentation Diagnosis Treatment Alveolar Echinococcosis Other Invasive Cestodes Prevention Key References References 290 Visceral Larva Migrans and Other Uncommon Helminth Infections Short View Summary Visceral Larva Migrans (Toxocariasis) Life Cycle in the Dog Infection in Humans Prevalence Clinical Manifestations Diagnosis Differential Diagnosis Treatment and Management Prevention Ocular Larva Migrans Baylisascariasis Anisakiasis Life Cycle in Marine Mammals Clinical Syndrome Laboratory Findings Diagnosis Treatment Prevention Cutaneous Larva Migrans (Creeping Eruption) Eosinophilic Meningitis Gnathostomiasis Life Cycle Clinical Manifestations Diagnosis Differential Diagnosis Treatment Prevention Abdominal Angiostrongyliasis Eosinophilic Gastroenteritis Dirofilariasis Capillariasis Swimmer’s Itch Key References References K Ectoparasitic Diseases 291 Introduction to Ectoparasitic Diseases Taxonomy of Ectoparasites Epidemiology of Ectoparasitic Diseases Mechanisms of Ectoparasite-Borne Diseases and Injuries Conclusions Key References References 292 Lice (Pediculosis) Short View Summary Epidemiology Diagnosis Clinical Manifestations and Differential Diagnosis Head Lice Body Lice Crab Lice (Pediculosis Pubis) Therapy Therapy for Pediculosis Capitis Therapy for Body Lice Prevention Key References References 293 Scabies Short View Summary Epidemiology Transmission Clinical Manifestations Diagnosis Therapy Prevention Conclusion Key References References 294 Myiasis and Tungiasis Short View Summary Myiasis Epidemiology Clinical Manifestations Therapy Prevention and Control Flea Infestations Tungiasis Epidemiology Clinical Manifestations Therapy Prevention and Control Key References References 295 Mites, Including Chiggers Short View Summary Mite Taxonomy and Ecology Epidemiology and Outcomes of Mite Infestations Diagnosis and Management of Mite Infections Delusional Mite and Other Ectoparasitic Infestations Prevention of Mite Infections and Mite-Transmitted Infectious Diseases Conclusion Key References References 296 Ticks, Including Tick Paralysis Short View Summary Tick Biology, Behavior, and Taxonomy Epidemiology of Tick-Borne Infectious Diseases Tick-Borne Bacterial Infections Spirochetal Infections (Borrelioses) Lyme Borreliosis Southern Tick-Associated Rash Illness (STARI) Tick-Borne Relapsing Fevers Spotted Fever Group Rickettsial Infections Q (Query) Fever Tularemia Tick-Borne Ehrlichioses and Anaplasmosis Tick-Borne Protozoal Infections Babesial Infections Tick-Borne Viral Infections Tick-Borne Viral Encephalitides New World TBEVs: Powassan Encephalitis Old World TBEVs Tick-Borne Hemorrhagic Fever Viruses Tick-Borne Coltiviruses Tick Paralysis Red Meat Allergy After Tick Bites Tick-Transmitted Coinfections Prevention and Control of Tick-Borne Infectious Diseases and Paralytic Poisonings Conclusions Key References References L Diseases of Unknown Etiology 297 Kawasaki Disease Short View Summary Epidemiology Etiology Clinical Manifestations Exanthem Conjunctival Injection Oropharyngeal Changes Peripheral Extremity Changes Cervical Lymphadenopathy Associated Clinical Features Arthritis Gastrointestinal Features Diagnosis Differential Diagnosis Pathology Genetics Therapy Cardiovascular Involvement Long-Term Outcome Key References References IV Special Problems A Nosocomial Infections 298 Infection Prevention and Control in the Health Care Setting Short View Summary Pathogen Transmission in the Hospital Hand Hygiene Disinfection and Sterilization (See Chapter 299) Environmental Cleaning and Disinfection Methods of Environmental Cleaning and Disinfection Water Management Transmission of Waterborne Pathogens Biofilms in Hospital Plumbing Legionnaires’ Disease Disinfection of Hospital Water Wastewater Plumbing Contamination Air Handling Air Handling for Airborne Infections Air Handling to Prevent Nosocomial Mold Infections Air Handling in the Operating Room Air Quality Transmission-Based Infection-Control Precautions Colonization Organisms Transmitted by Contact Organisms Transmitted by Droplet Organisms Transmitted by the Airborne Route Organisms Transmitted by Aerosol Device-Related Infections Ventilator-Associated Pneumonia (See Chapter 301) Measures to Prevent Ventilator-Associated Pneumonia Selective Oral and Digestive Decontamination Ventilator-Associated Events “Bundled” Ventilator-Associated Pneumonia Prevention Strategies Central Venous Catheter–Associated Infections (See Chapter 300) Preventive Measures for Catheter Insertion Preventive Measures for Catheter Maintenance Chlorhexidine Gluconate Daily Baths “Bundled” Catheter-Associated Bloodstream Infection–Prevention Strategies Catheter-Associated Urinary Tract Infections (See Chapter 302) Measures to Prevent Catheter-Associated Urinary Tract Infections Surveillance Active Microbial Surveillance Decolonization and Skin Antisepsis Management of Nosocomial Transmission of Multidrug-Resistant Organisms Typing of Isolates Surveillance and Public Health Reporting Outbreak Investigation Special Situation: Varicella-Zoster Virus Exposure Investigation Management of Exposed Patients Management of Exposed Personnel Occupational Medicine Preexposure Screening Preexposure Immunizations Influenza Immunization Preventing Transmission of Respiratory Viruses to Patients Universal and Standard Precautions Postexposure Prophylaxis Management of Occupational Exposure to Human Immunodeficiency Virus Postexposure Testing and Follow-Up Emerging Infectious Diseases Key References References 299 Disinfection, Sterilization, and Control of Hospital Waste Definition of Terms Rational Approach to Disinfection and Sterilization Critical Items Semicritical Items Noncritical Items Disinfection of Health Care Equipment and Surfaces Chemical Disinfectants Alcohol Chlorine and Chlorine Compounds Glutaraldehyde Hydrogen Peroxide Improved Hydrogen Peroxide Iodophors Ortho-phthalaldehyde Peracetic Acid Peracetic Acid With Hydrogen Peroxide Phenolics Quaternary Ammonium Compounds Pasteurization Ultraviolet Light Sterilization Steam Sterilization Immediate-Use Steam Sterilization Ethylene Oxide “Gas” Sterilization Hydrogen Peroxide Gas Plasma Vaporized Hydrogen Peroxide Hydrogen Peroxide Plus Ozone Current Issues in Sterilization Inactivation of Creutzfeldt-Jakob Disease Agent Disinfection High-Level Disinfection of Semicritical Items Current Issues With High-Level Disinfection of Semicritical Items Reprocessing Endoscopes: A Shift From Disinfection to Sterilization Inactivation of Human Papilloma Virus Immersion Versus Perfusion of Channel Scopes Such as Cystoscopes Ultrasound Probe Disinfection With Vaporized Hydrogen Peroxide Low-Level Disinfection of Noncritical Environmental Surfaces and Patient Care Equipment Adequacy of Room Cleaning and Disinfection With Chemical Germicides Improving Room Cleaning and Disinfection, and Demonstrating the Effectiveness of Surface Decontamination in Reducing Health Care–Associated Infections “No-Touch” Methods for Room Decontamination Ultraviolet Light for Room Decontamination Hydrogen Peroxide Systems for Room Decontamination Comparison of Ultraviolet Irradiation Versus Hydrogen Peroxide for Room Decontamination Continuous Room Decontamination Surface Disinfection: Treatment Time (Wipes/Sprays) Versus Contact Time (Liquids) OSHA Bloodborne Pathogen Standard Emerging Pathogens, Antibiotic-Resistant Bacteria, and Bioterrorism Agents Control of Hospital Waste Conclusion Acknowledgments Key References References 300 Infections Caused by Percutaneous Intravascular Devices Short View Summary Pathogenesis Contamination of the Infusate Contamination of the Catheter Hub and Lumen (Intraluminal Source) Contamination of Skin at the Device Insertion Site (Extraluminal Source) Epidemiology CLABSI Rates Patient-Related Issues Catheter-Related Issues Hospital-Related Issues Microbiology Diagnosis Device-Specific Issues Peripheral Intravenous Cannulization Central Venous Catheters Short-Term Issues Parenteral Nutrition Issues Long-Term Issues Peripherally Inserted Central Venous Catheters Care and Maintenance of Implanted Central Venous Catheters Pulmonary Artery Catheters Arterial Lines, Transducers, and Transducer Domes Treatment of CLABSIs Antimicrobial Lock Therapy Prevention of Device-Associated Bacteremia Before Insertion of Vascular Catheters At Insertion After Insertion Special Approaches for the Prevention of CLABSIs Antimicrobial Prophylaxis Antimicrobial Lock Prophylaxis Antimicrobial Catheters Other Prevention Issues Key References References 301 Nosocomial Pneumonia Short View Summary Health Care–Associated Pneumonia Epidemiology Morbidity and Mortality Pathophysiology Risk Factors Diagnosis Clinical Pulmonary Infection Score Summary and Recommendations for Clinical Diagnosis Microbiologic Evaluation Invasive Versus Noninvasive Respiratory Tract Sampling Microbiology Treatment Empirical Therapy Vancomycin Versus Linezolid for MRSA Coverage Combination Versus Monotherapy for Gram-Negative Pathogens Aerosolized Versus Intravenous Drug Delivery Tailoring and Deescalating Therapy Duration of Therapy Prevention Ventilator-Associated Pneumonia Prevention Bundles Ventilator-Assisted Pneumonia as A Quality Metric Key References References 302 Health Care–Associated Urinary Tract Infections Short View Summary Definitions Epidemiology Incidence and Prevalence CAUTI Risk Factors Complications Microbiology Pathogenesis Diagnosis Significant Bacteriuria Symptoms and Signs Pyuria Prevention Prevention Strategies That Should Be Routine Prevention Components of Infection Control Programs Reduction of Unnecessary Catheterization Alternatives to Indwelling Urethral Catheterization Condom Catheterization Intermittent Catheterization Suprapubic Catheterization Techniques for Catheter Insertion and Maintenance Bundled CAUTI Prevention Programs Prevention Strategies With Possible Benefit Antiseptic- and Antimicrobial-Coated Catheters Prophylaxis With Antimicrobial Agents Systemic Antimicrobials Methenamine Salts Prevention Strategies With Little Benefit Enhanced Meatal Care Cranberry Products Bladder Irrigation With Antimicrobial Therapy or Saline Antimicrobial Drugs in the Drainage Bag Routine Catheter Change Prophylactic Antimicrobial Therapy at Catheter Removal or Replacement Preclinical Strategies for CAUTI Prevention Health Care–Associated Asymptomatic Bacteriuria Routine Screening and Treatment Prevention of Overtreatment of Asymptomatic Bacteriuria in Health Care Settings Management of Health Care–Associated Urinary Tract Infection Urine Culture and Catheter Replacement Before Treatment Choice of Antimicrobial Agent Duration Nephrostomy Tubes and Ureteral Stents Fungal Urinary Tract Infection Summary Key References References 303 Health Care–Acquired Hepatitis Short View Summary Historical Background Current Epidemiology of Health Care–Associated Hepatitis B and C Outbreaks in the United States Fecal-Oral Transmission Hepatitis A Hepatitis E Seroprevalence of Hepatitis E in Developed Countries and Risk of Bloodborne Transmission Other Nosocomial Transmission Hepatitis B Epidemiology Incidence After Exposure Reported Transmissions Worker-to-patient transmission. Patient-to-worker transmission. Dialysis setting. Other nosocomial transmissions. Vaccine Acceptance and Response Among Health Care Workers, and Duration of Immunity Postexposure Management Hepatitis C Seroprevalence Incidence After Occupational Exposure Reported Transmissions Worker-to-patient transmission. Transmission in dialysis setting. Solid tumor transplantation. Other nosocomial transmissions. Management Hepatitis D Key References References 304 Transfusion- and Transplantation-Transmitted Infections Short View Summary Transfusion-Associated Infections Scope of Blood Transfusion Bloodborne Pathogens Human Immunodeficiency Virus Type 1 Human Immunodeficiency Virus Type 2 Human T-Cell Lymphotropic Virus Types 1 and 2 Other Retroviruses Hepatitis B and D Viruses Hepatitis C Virus Hepatitis A Virus Hepatitis E Virus West Nile Virus and Other Arboviruses Herpesviruses Parvovirus B19 Non–A-E Hepatitis Bacterial Pathogens Red Blood Cells Platelets Other Agents Transmitted Through Blood Components Tick-borne Bacteria Parasites Prions Infectious Diseases Transmitted Through Transplantation of Solid Organs and Other Tissues Organ Transplant–Transmitted Bloodborne Pathogens Pathogens Causing Encephalitis Strongyloidiasis Microsporidiosis Ehrlichiosis Key References References B Infections in Special Hosts 305 Infections in the Immunocompromised Host Components of Host Defense Cellular and Humoral Immunity Innate Immunity Granulocytes Monocytes and Macrophages Natural Killer Cells Impact of Treatment on Cellular Immunity Impact of Treatment on Humoral Immunity Humoral Immunity and the Spleen Platelets The Integument as Host Defense Skin Respiratory Tract Alimentary Tract and Normal Microbiota as Host Defense Dysbiosis Mucosal Barrier Injury Nutritional Status Comorbidity and Host Defense Fever and the Inflammatory Response Systemic Inflammatory Response Syndrome, Immune Reconstitution Inflammatory Syndrome, and Host-Directed Therapy (See Chapters 49 and 73) Infections by Site Bacteremia Bacteremia Related to Intravascular Catheters Bacteremia From the Gastrointestinal Tract Oral Cavity Infections Respiratory Tract Infections Skin Infections Gastrointestinal Tract Infections Urinary Tract Infections Central Nervous System Infections Liver Infections Sequence of Infections Role of Molecular Diagnostics in Infections in the Immunocompromised Host Conclusion Key References References 306 Prophylaxis and Empirical Therapy of Infection in Cancer Patients Short View Summary Epidemiology and Risk Factors for Infections in Cancer Patients Neutropenia Mucositis and Microbiota Alterations Central Venous Catheters Genetic Factors New Therapies Biologic Agents and Other New Drugs Chimeric Antigen Receptor T-Lymphocyte Therapy Surgery Etiology Bacterial Infections Fungal Infections Viral Infections Other Pathogens Prevention of Infections in Cancer Patients Prevention of Bacterial Infections Antibacterial Chemoprophylaxis Decolonization for Prevention of Infections Due to Resistant Bacteria, Including Fecal Microbiota Transplantation Prophylaxis of Tuberculosis Prevention of CVC-Related Infections (See Chapter 300) Prevention of Fungal Infections Primary Antifungal Chemoprophylaxis Secondary Antifungal Prophylaxis Prophylaxis Against Pneumocystis jirovecii Prevention of Viral Infections Other Prophylactic Measures Role of Colony-Stimulating Factors in Prophylaxis Role of Immunoglobulins in Prophylaxis Infection Control: Isolation and Antimicrobial Stewardship Food and Lifestyle Vaccination Treatment of Complications in Neutropenic Cancer Patients Empirical Antibacterial Therapy of Fever During Neutropenia Patients at Low Risk Patients at High Risk Duration of Antibacterial Treatment Empirical and Preemptive (Diagnostic-Oriented) Antifungal Therapy Management of a Neutropenic Patient With a Localized Infection Catheter-Related Infection Pneumonia Abdominal Infections Other Treatments Granulocyte Transfusions Colony-Stimulating Factors Conclusions Key References References 307 Infections in Recipients of Hematopoietic Stem Cell Transplants Short View Summary Basic Transplantation Techniques Chemotherapy Irradiation Reduced-Intensity Conditioning or Nonmyeloablative Transplantation Human Leukocyte Antigen Matching Prevention of Infection Clinical Syndromes Unique to the Hematopoietic Stem Cell Recipient Hemorrhagic Cystitis (HC) Venoocclusive Disease (Sinusoidal Obstruction Syndrome) Graft-Versus-Host Disease Hepatitis Pneumonia Syndromes Diarrhea Rash Osteomyelitis Patterns of Immunosuppression at Different Times After Myeloablative HSCT Preengraftment Risk Period Postengraftment Risk Period Late Risk Period Immunodeficiency After Nonmyeloablative HSCT Measures to Reduce Risks for Infection Natural History of Individual Infections After HSCT Bacterial Infections Encapsulated Bacteria Viridans-Group Streptococci Clostridioides difficile Mycobacteria Intracellular Bacteria Viral Infections Herpes Simplex Virus Cytomegalovirus Varicella-Zoster Virus Adenovirus Norovirus Respiratory Viruses Epstein-Barr Virus Human Herpesvirus 6 Parvovirus Fungal Infections Pneumocystis Candida Aspergillus Other Yeasts Other Molds Parasitic Infections Methods of Immune System Reconstitution After HSCT Vaccination Immunoglobulin Replacement Key References References 308 Infections in Solid-Organ Transplant Recipients Fundamentals of Immunosuppressive Therapy Corticosteroids Antimetabolite Agents Calcineurin Inhibitor Agents Mammalian Target of Rapamycin Inhibitors Biologic Agents Pretransplant Evaluation for Infections Transplant Candidates Colonized With Multidrug-Resistant Bacteria Selective Testing for Specific Infections in Transplant Candidates Time of Occurrence of Infections After Transplantation Infections in First 30 Days Infections Between 30 to 180 Days Infections Occurring 6 Months or Later Unique Characteristics of Infections in Different Types of Transplants Kidney Transplant Recipients Heart Transplant Recipients Lung and Heart-Lung Transplant Recipients Invasive Aspergillosis After Lung Transplantation Liver Transplant Recipients Abdominal Infections After Liver Transplantation Fungal Infections After Liver Transplantation Pancreas Transplant Recipients Small Bowel Transplant Recipients Specific Sites and Types of Infection Infections of the Skin and Surgical Site Infections of the Urinary Tract Infections of the Bloodstream Pulmonary Infections Tuberculosis Diagnostic Considerations Management of Tuberculosis Treatment of Latent Tuberculosis Treatment of Active Tuberculosis Pulmonary Infections Due to Endemic Mycoses Coccidioidomycosis Histoplasmosis Abdominal and Gastrointestinal Infections Diarrhea Central Nervous System Infections Specific Problems of Viral Infections Cytomegalovirus Risk Factors Clinical Manifestations Laboratory Diagnosis and Immune Monitoring Prevention Treatment Epstein-Barr Virus and Posttransplantation Lymphoproliferative Disorder Immunobiology Risk Factors Clinical Manifestations and Diagnosis Prevention and Treatment Herpes Simplex Virus Varicella-Zoster Virus Human Herpesviruses 6 and 7 Human Herpesvirus 8 (Kaposi Sarcoma Herpesvirus) Human Immunodeficiency Virus Human Immunodeficiency Virus Screening Human Immunodeficiency Virus–to–Human Immunodeficiency Virus Transplantation RNA Respiratory Viruses Polyomaviruses Adenovirus Parvovirus B19 Zika Virus Norovirus Hepatitis Viruses Hepatitis A Virus Hepatitis B Virus Liver Transplant Candidates and Recipients Nonliver Organ Transplant Candidates and Recipients Hepatitis C Virus Hepatitis E Virus Donor-Transmitted Infections (See Chapter 304) Donor-Derived Bacterial Infections Donor-Derived Fungal Infections Other Pathogens With Potential for Transmission With the Allograft Approach to Fever in the Transplant Recipient Fever Without an Evident Source Vaccination in Organ Transplant Candidates and Recipients Selected Specific Vaccines Influenza Pneumococcus Herpes Zoster Hepatitis B Hepatitis C Acknowledgment Key References References 309 Infections in Patients With Spinal Cord Injury Short View Summary Factors That Predispose to Infection Challenges in Evaluating Patients for Infection Urinary Tract Infection Pneumonia Infection of Pressure Sores Osteomyelitis Bloodstream Infection Intraabdominal Infection Multiresistant Organisms in the Spinal Cord Injury Setting Clostridioides difficile (Formerly Clostridium difficile) References 310 Infections in Older Adults Short View Summary Predisposition of Older Adults to Infection Comorbid Illness Waning Immunity With Age (Immune Senescence) Nutrition Social and Environmental Factors Presentation of Infection in Seniors Antibiotic Management in Seniors Antimicrobial Treatment Antibiotic Stewardship Antibiotics at the End of Life Age-Related Differences in Specific Clinical Syndromes Pneumonia Urinary Tract Infection Bacteremia and Sepsis Infective Endocarditis Prosthetic Device Infections Gastrointestinal Infections Tuberculosis Human Immunodeficiency Virus Fever of Unknown Origin Immunization of Older Adults Pneumococcal Vaccine Influenza Zoster Other Vaccines Travel Recommendations for Older Adults Key References References 311 Infections in Asplenic Patients Short View Summary Anatomy of the Spleen Function of the Spleen Regulation of Inflammation Filtration and Clearance Adaptive Immunity Innate Immunity Hematopoiesis/Hemostasis Types of Asplenia Congenital Asplenia Acquired Asplenia Acquired Hyposplenia Assessment for Splenic Function Epidemiology and Risk Factors of Sepsis in Asplenic Patients Clinical Presentation of Sepsis Secondary to Asplenia Microbial Agents Causing Postsplenectomy Sepsis Bacteria Protozoa Diagnosis of Postsplenectomy Sepsis Management of Postsplenectomy Sepsis Prevention of Postsplenectomy Sepsis Prophylactic Antibiotics Vaccines Patient Education Key References References 312 Infections in Injection Drug Users Short View Summary Host Defenses Immune Changes Skin and Soft Tissue Infections Infection Sites Abscess Microbiology of Abscesses Diagnosis of Abscess Management of Soft Tissue Infections Skin Ulcers Necrotizing Fasciitis Pyomyositis Injection Anthrax Bone and Joint Infections Epidemiology of Skeletal Infections Site of Skeletal Infection Diagnosis and Management of Skeletal Infections Bacteremia and Infective Endocarditis Epidemiology Microbiology Pathophysiology Clinical Manifestations Diagnosis Therapy Prognosis Noncardiac Vascular Infections Septic Thrombophlebitis Mycotic Aneurysm Pulmonary Infections Pathophysiology Clinical Patterns Tuberculosis in Injection Drug Users Hepatitis Risk Factors Hepatitis B Delta Virus Hepatitis C Hepatitis A Hepatitis E Splenic Abscess Clinical Manifestations Therapy Central Nervous System Infections Risk Factors Cerebral Mycotic Aneurysm Brain Abscess and Subdural Empyema Meningitis Spinal Epidural Abscess Tetanus and Wound Botulism Ocular Infections Endophthalmitis Human Immunodeficiency Virus Infection Epidemiology Prevention Therapy and Prognosis Sexually Transmitted Diseases Epidemiology Syphilis Key References References 313 Surgical Site Infections and Antimicrobial Prophylaxis Short View Summary Historical Background Principles of Surgical Site Infection Prevention Determinants and Pathophysiology Species and Sources of Wound Bacteria Virulence Factors of Major Wound Pathogens Clean Wound Infections Contaminated Wound Infections Wound Microenvironment and Operative Effects on Immunity Foreign Material and Operative Trauma to Tissue Effect of Operative Procedures on Systemic and Local Immunity Risk Factors for Surgical Site Infections Patient Factors Procedural and Proceduralist Factors Postoperative Factors Prevention of Surgical Site Infections General Concepts Perioperative Antimicrobial Prophylaxis Antimicrobial Prophylaxis: Drug Selection and Dosing Basic Principles Drug Selection With Rising Incidence of Antibiotic-Resistant Pathogens (e.g., MRSA) Methicillin-Resistant S. aureus–Specific Prophylaxis Special Considerations With Prophylaxis in Colorectal Surgery Dosing in Obese Patients Antimicrobial Prophylaxis: Timing of Administration and Redosing Initial Dose Timing Intraoperative Redosing Antimicrobial Prophylaxis: Duration Novel Methods of Antimicrobial Prophylaxis: Local and Topical Compounds Adverse Effects of Prophylaxis Cost-Benefit of Prophylaxis Use of Surgical Prophylaxis Compliance as a Reported Measure of Health Care Quality Surgical Site Infection Surveillance Postdischarge Surgical Site Infection Surveillance Key References References C Surgical- and Trauma-Related Infections 314 Burns Short View Summary Burn Injury Types of Injuries Admitted to Burn Centers Epidemiology Survival in Burn Injury Infectious Complications of Burn Injury Microbiology Pathogenesis and Microbial Evolution of Burn Wound Colonization and Infection Fungal Colonization and Infection Following Burn Injury Viral Infections Following Burn Injury Diagnosis Defining Infection in Burn Patients Sepsis and Bloodstream Infections Pneumonia Wound Infections Treatment Empirical Therapy of Infections Dosing of Antimicrobials in Burns Antifungal Therapy Surgical Management and Topical Therapy Prevention Infection Prevention and Health Care–Associated Infections Antimicrobial Stewardship in the Burn Unit Other Strategies to Modify Infection Risk Conclusions Key References References 315 Bites Short View Summary Animal Bites Management of Animal Bites Venomous Snakebites Lip Wounds and Paronychia Human Bites Management of Human Bites Clenched-Fist Injuries Key References References D Immunization 316 Immunization Immunologic Basis of Vaccination Determinants of Immunogenicity Live Versus Killed or Subunit Vaccines Dose Adjuvants Route of Administration Age Components of the Immune Response Mobilization of the Adaptive Immune Response Unanticipated Responses Temporal Course of the Immune Response Measurement of the Immune Response Vaccine Development General Principles of Immunization Currently Available Immunizing Agents Vaccines Adenovirus Vaccine Anthrax Vaccine Bacillus Calmette-Guérin Vaccine Cholera Vaccine Diphtheria Toxoid Haemophilus influenzae Type b Vaccine (Hib) Hepatitis A Vaccine Hepatitis B Vaccine Human Papillomavirus Vaccines Influenza Virus Hemagglutinin Vaccines–Inactivated and Recombinant (IIV and RIV) Live-Attenuated Influenza Vaccine Japanese Encephalitis Measles-Containing Vaccine Meningococcal Vaccines Mumps Vaccine Pertussis-Containing Vaccine Plague Vaccine Pneumococcal Polysaccharide Vaccine Pneumococcal Conjugate Vaccine Polio Vaccine Rabies Vaccine Rotavirus Vaccines Rubella Vaccine Smallpox Vaccine Tetanus Toxoid Typhoid Vaccine Varicella Vaccine Yellow Fever Vaccine Zoster Vaccine Immunoglobulin Preparations Intramuscular Immune Globulin Indications for Use of Intramuscular Immune Globulin Replacement therapy for antibody deficiency disorders. Hepatitis A prophylaxis. Measles prophylaxis. Specific Intramuscular Immune Globulin Preparations Hepatitis B immune globulin. Rabies immune globulin. Tetanus immune globulin. Varicella-zoster immune globulin. Immune Globulin Intravenous Indications for Use of Immune Globulin Intravenous Specific Immune Globulins for Intravenous Use Vaccinia Immune Globulin Respiratory Syncytial Virus Immune Globulin and Palivizumab Adverse Reactions to Immune Globulin Preparations Immune Globulin Subcutaneous Rh Immune Globulin Use of Vaccines Routine Children Adolescents Adults Special Circumstances Travel Occupational Exposure Pregnancy Immunocompromised States Human Immunodeficiency Virus Postexposure Immunization Other Considerations Storage and Handling of Vaccines Assessing the Need for Immunization Immunization Records Parent and Patient Education Simultaneous Administration and Intervals Between Immunizations Combination Vaccines Interrupted Schedules Reporting of Disease and Adverse Events Compensation for Vaccine Injuries Standards for Immunization Practices Methods to Improve Immunization Coverage Sources of Information Key References References E Zoonoses 317 Zoonoses Short View Summary One Health Initiative Mechanisms of Transmission Factors in the Emergence of Zoonotic Diseases Prediction and Early Detection of Emerging and Reemerging Zoonotic Diseases Zoonotic Diseases Infections Associated With Wildlife Bats Rodents Diseases Associated With Agricultural and Other Domestic Animals Conclusions References F Protection of Travelers 318 Protection of Travelers Short View Summary Epidemiology of Travel-Related Illness Immunization Update of Routine Immunizations Tetanus-Diphtheria–Acellular Pertussis Measles-Mumps-Rubella Influenza and Pneumococcal Vaccine Varicella Vaccines to Consider for All Destinations in the Developing World Hepatitis A Hepatitis B Combination Hepatitis A and Hepatitis B Vaccine Typhoid Vaccines to Consider Only for Certain Destinations Yellow Fever Risk of Yellow Fever Yellow Fever Entry Requirements Yellow Fever Booster Doses Meningococcal Disease Rabies Japanese Encephalitis Polio Cholera Tick-Borne Encephalitis Spacing and Interactions of Travel-Related Vaccines Malaria Chemoprophylaxis Epidemiology of Malaria in Travelers Risk of Travelers’ Malaria Choice of Malaria Chemoprophylactic Drugs Adverse Effects of Antimalarial Drugs Prevention of Plasmodium vivax and Plasmodium ovale Relapses Standby Therapy Instead of Continuous Prophylaxis Dengue Chikungunya and Zika Virus Traveler’s Diarrhea Risk and Etiology Prevention Self-Treatment Key Preventive Behaviors Personal Protection Against Arthropods Protection Against Foodborne Disease Sex Protection Against Bloodborne Disease Protection Against Skin Diseases Protection Against Pathogens Encountered by Swimming and Water Exposure Prevention of Tuberculosis Noninfectious Travel Problems Medical Kit and Medical Care Abroad Air Travel–Related Morbidity Deep Venous Thrombosis/ Pulmonary Embolism Jet Lag, Motion Sickness, and In-Flight Medical Emergencies Altitude Traveling Adults With Special Needs Immunocompromised Travelers and Human Immunodeficiency Virus–Infected Travelers Pregnant Travelers Key References References 319 Infections in Returning Travelers Short View Summary Fever Epidemiology History Detailed Travel Itinerary Chronology of Travel and Illness Exposures Immunization History Antimalarial Prophylaxis or Treatment Other Medications Ingested Physical Examination Considerations for the Common Travel-Related Febrile Illnesses Malaria Dengue Chikungunya Fever Zika Virus Typhoid and Paratyphoid Fever Viral Hepatitis Rickettsial Disease Leptospirosis Respiratory Illness Special Consideration of Ebola Virus Disease in Returning Travelers Yellow Fever in Returning Travelers Initial Office Approach to the Febrile Patient Diarrhea in Travelers Acute Traveler’s Diarrhea Persistent Diarrhea in the Traveler Skin Problems Eosinophilia Screening for Asymptomatic Infection Key References References Copyright Title Page Dedication Contents Chapter 1: ‘I’m thinking’ – Oh, but are you? Chapter 2: Renegade perception Chapter 3: The Pushbacker sting Chapter 4: ‘Covid’: The calculated catastrophe Chapter 5: There is no ‘virus’ Chapter 6: Sequence of deceit Chapter 7: War on your mind Chapter 8: ‘Reframing’ insanity Chapter 9: We must have it? So what is it? Chapter 10: Human 2.0 Chapter 11: Who controls the Cult? Chapter 12: Escaping Wetiko Postscript Appendix: Cowan-Kaufman-Morell Statement on Virus Isolation Bibliography Index
