(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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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