Updates on Clostridioides difficile in Europe: Advances in Microbiology, Infectious Diseases and Public Health Volume 18 (Advances in Experimental Medicine and Biology, 1435)

This fully updated second edition outlines the currently available clinical, epidemiological and experimental data on Clostridioides difficile infections(CDI) with special emphasis on studies and results achieved in Europe. The incidence and severity of CDI has increased significantly over the last decade, and the book explains why C. difficile, recently reclassified as Clostridioides difficile, remains a significant challenge, also from economic perspective, to health care systems all over the world. The different reservoirs of this ubiquitous microorganism are reviewed as well as the different factors contributing to its virulence, such as toxins and biofilm formation. The rapid evolution of antibiotic resistance is clearly a concern and in a specific way can influence the CDI epidemiology. Additionally, new emerging strains and comparative genomics studies are taken into consideration for their relevance from epidemiological and evolutionary point of view. The book also gives an overview on diagnostics, therapy and surveillance, all of which are still challenging. Therefore, a closer look is taken on the effect of probiotics as an alternative to antibiotics, for prevention and treatment of CDI. Fecal transplantation from healthy donors, passive immunotherapies and vaccines for patients with recurrences are also discussed in dedicated chapters. New topics included sporulation and membrane vesicles in C. difficile. The book closes with a summary of the history and the achievements of the European Society of Clinical Microbiology and Infectious Diseases Study Group for Clostridium difficile (ESGCD) written by the current and past presidents of the Society. It is the aim of this book to raise awareness on CDI and to disseminate updated information on its prevention, diagnosis and treatment. Preface Contents Economic Burden of Clostridioides difficile Infection in European Countries 1 Introduction 2 Economic Burden of Hospital-Acquired CDI in European Countries 2.1 Primary Episodes 2.1.1 Northern Europe 2.1.2 Western Europe 2.1.3 Southern Europe 2.2 Recurrent Episodes 2.3 Length of Stay 2.4 Distribution of Costs 3 Economic Burden of Community-Acquired CDI 4 Pediatric Population 5 Economic Costs of CDI Outbreaks References The Need for European Surveillance of CDI 1 Epidemiology of CDI in Europe 2 Developments in Approaches to Monitoring the Epidemiology of CDI in European Countries 3 Clinical Suspicion and Diagnostic Testing: A Prerequisite for Surveillance 4 Whole-Genome Sequencing-Based Typing as a Tool for In-Depth Analysis of the Epidemiology of CDI 5 Benefits of National Surveillance Programmes: Experiences from The UK and Ireland 5.1 C. difficile Infection in Ireland 5.2 C. difficile Infection in the UK 6 Epidemiological Sentinel Surveillance 7 European CDI Surveillance at the ECDC 8 The Need for European Surveillance of CDI 9 Conclusion References Diagnostic Guidance for C. difficile Infections 1 Introduction 2 Reference Tests 3 Rapid Assays 4 Recommended Testing Algorithms 5 Selection of Stool Samples 6 Repeat Testing 7 Consequences of Testing Strategy on CDI Incidence/Reporting Rates 8 Non-microbiological Diagnostic Tests and Procedures 8.1 CT Imaging 8.2 Endoscopy 8.3 Histopathology 9 Alternative Testing Strategies 9.1 Calprotectin 9.2 Lactoferrin 9.3 Faecal Leukocyte Test 9.4 Interleukins and Chemokines 9.4.1 Interleukins and Chemokines to Discriminate CDI Patients 9.4.2 Interleukins and Chemokines to Discriminate CDI Severity and Predict Outcome 9.5 Microbiota-Based Markers for Prediction or Diagnostic of Clostridioides difficile Infection References European Practice for CDI Treatment 1 Introduction 2 ESCMID Guidelines for CDI Treatment 2.1 Non-severe CDI 2.2 Definition and Treatment of Severe CDI 2.3 Recurrent CDI 2.4 CDI Prophylaxis 3 Updated Survey of European CDI Experts on CDI Treatment 4 Clostridioides difficile Pipeline Prophylactic and Therapeutic Agents 4.1 Surotomycin and Cadazolid 4.2 Ridinilazole 4.3 CDI Prophylaxis 4.3.1 Ribaxamase 4.3.2 DAV132 4.4 Active C. difficile Immunisation 4.5 Microbiome-Based Therapeutics 4.5.1 Faecal Microbiota Transplantation 4.5.2 Live Biotherapeutic Microbiota Preparations 4.5.2.1 RBX2660 4.5.2.2 SER-109 4.5.2.3 Non-toxigenic C. difficile 5 Summary References Fecal Microbiota Transplantation as Emerging Treatment in European Countries 2.0 1 Introduction 2 Fecal Microbiota Transplantation for Clostridioides difficile Infection 2.1 The Burden of Clostridioides difficile 2.2 Fecal Microbiota Transplantation and Clostridioides difficile 2.3 FMT Centers in Europe 2.4 Stool Banks 2.5 FMT, New Perspectives 2.6 FMT as First-Line Therapy for CDI? 2.7 Fecal Microbiota Transplantation for Inflammatory Bowel Disease References Probiotics for Prevention and Treatment of Clostridium difficile Infection 1 Introduction 2 Clinical Studies Evaluating Probiotic Efficacy 3 Models to Study Probiotics Against C. difficile 4 Mechanisms of Probiotic Action 4.1 Microbial Antagonism: Interaction Probiotics vs. C. difficile 4.2 Probiotics Against C. difficile Toxin Activity 4.3 Other Mechanisms of Action 5 Conclusion and Future Trends References Immunization Strategies Against Clostridioides difficile 1 Introduction 2 Virulence Factors and Host Immune Response 2.1 Surface Proteins and Colonization Factors 2.1.1 Cell Wall Proteins (Cwp) 2.1.2 Flagellar Proteins 2.1.3 Other Surface Components 2.2 Toxins 2.2.1 TcdA and TcdB 2.2.2 Binary Toxin 2.3 Host Antibody Response Against C. difficile 3 Passive Immunization Strategies with Antibody-Based Products 3.1 Assays in Animal Models 3.1.1 Parenteral Administration of Antibody-Based Products in Animal Models 3.1.2 Mucosal Administration of Antibody-Based Products in Animal Models 3.2 Assays in Humans and Clinical Trials 3.2.1 Parenteral Administration of Antibody-Based Products in Humans 3.2.2 Mucosal Administration of Antibody-Based Products in Humans and Clinical Trials 4 Active Immunization Strategies: Vaccines 4.1 Vaccines Targeting Toxins 4.1.1 In Animal Models 4.1.2 In Humans and Clinical Trials 4.2 Vaccines Targeting Surface Components 5 Conclusion References Ribotypes and New Virulent Strains Across Europe 1 Introduction 2 C. difficile Typing Methods 2.1 PCR Ribotyping 2.2 Other Methods Used for C. difficile Typing 3 Global Distribution of C. difficile PCR Ribotypes in Europe 4 Emerging PCR Ribotypes 4.1 PCR Ribotype 176 4.2 PCR Ribotype 078 4.3 PCR Ribotype 126 4.4 PCR Ribotype 033/Toxinotype XI 4.5 PCR Ribotype 018 4.6 PCR Ribotype 017 4.7 Other Emerging PCR Ribotypes 4.8 Emerging Strains with a A+B-CDT- Unusual Profile 5 C. difficile Infection in the Community 6 Conclusion References Antibiotic Resistances of Clostridioides difficile 1 Introduction 2 C. difficile Antibiotic Susceptibility 2.1 Antibiotics Associated with CDI 2.2 Antibiotics for CDI Treatment 3 Multidrug Resistance in C. difficile 4 C. difficile Antibiotic Susceptibility Methods 5 C. difficile Mechanisms of Resistance 5.1 Antibiotics Associated with CDI 5.2 Antibiotics for CDI Treatment 5.3 Other Antibiotics 6 Conclusions References Comparative Genomics of Clostridioides difficile 1 Introduction 2 Global Comparative Genomics 2.1 Population Structure of C. difficile Species 2.2 Worldwide Evolution of Important C. difficile PCR Ribotypes 2.2.1 Epidemic C. difficile PCR Ribotype 027 2.2.2 Toxin Variant C. difficile PCR Ribotype 017 2.3 C. difficile Transmissions and Epidemiology of Recurrent CDI 2.3.1 C. difficile Transmissions in the Hospital Environment 2.3.2 C. difficile Recurrence: Reinfections Versus Relapses 2.4 Influence of SNPs on Virulence and Phenotype of CD630 Derivatives 2.5 Comparative Genomic Analysis of Non-toxigenic Strains 3 Targeted Comparative Genomics 3.1 Evolution of the C. difficile Pathogenicity Locus 3.1.1 PaLoc Acquisition and Exchange 3.1.2 PaLoc Organization and Evolution 3.2 Advances in CRISPR/Cas Systems and Phage-Host Interaction 3.2.1 CRISPR Mechanism and Physiology 3.2.2 CRISPR Distribution and Diversity 4 Conclusions References An Updated View on the Cellular Uptake and Mode-of-Action of Clostridioides difficile Toxins 1 Introduction 2 Structure, Uptake and Mode-of-Action of C. difficile Toxins A and B 2.1 Modular Composition of C. difficile Toxins A and B 2.1.1 The CROP Domain 2.1.2 The Glucosyltransferase Domain (GTD) 2.1.3 The Cysteine Protease Domain (CPD) 2.1.4 Delivery and Receptor-Binding Domain (DRBD) 2.1.4.1 Translocation Domain (TD) of DRBD 2.1.5 Receptor-Binding Domain of DRBD 2.1.6 Structural Information on the Modular Composition of Toxins A and B 2.2 Binding and Uptake of C. difficile Toxins A and B 2.2.1 Host Receptors of Toxins A and B 2.2.2 Endocytic Pathways for the Cellular Uptake of Toxins A and B 2.2.3 Delivery of the GTD into the Cytosol 2.3 Mode-of-Action of Toxins A and B 2.3.1 Glucosylation-Dependent Effects and Consequences 2.3.2 Glucosylation-Independent Effects of Toxins A and B 2.4 Relative Importance of Toxins A and B in Clostridioides difficile Infection 3 Structure, Uptake and Mode-of-Action of the Binary C. difficile Transferase (CDT) 3.1 Bipartite Composition of CDT 3.1.1 The Binding Component of CDT 3.1.2 The Enzyme Component of CDT 3.2 Binding and Uptake of CDT 3.2.1 The Lipolysis-Stimulated Lipoprotein Receptor 3.2.2 Endocytic Pathways for the Cellular Uptake of CDT 3.2.3 Role of Chaperones During the Cellular Uptake of CDT 3.3 Mode-of-Action of CDT 3.4 Role of CDT During C. difficile Infection 4 Conclusions References Clostridioides difficile Biofilm 1 Introduction 2 Main Features of C. difficile Biofilm 3 Genetic Factors Behind C. difficile Biofilm Formation 4 In Vitro and In Vivo Models to Study the Interactions of Sessile Microorganisms 5 Effects of Antibiotics on C. difficile Biofilm 6 Alternatives to Counteract Biofilm-Growing C. difficile 7 Conclusions References Clostridioides difficile Sporulation 1 Importance of Spores in the Clostridioides difficile Life Cycle 2 Making a Dormant Cell Inside Another Cell 3 The Genetic Regulation of Sporulation in C. difficile 3.1 Regulatory Networks, an Overview 3.2 Sporulation Initiation 3.2.1 Regulatory Events in the Cell Entering Sporulation 3.2.2 Morphological Changes in Cells Entering Sporulation 3.3 Cell Type-Specific Gene Expression 3.3.1 The sigmaF Checkpoint 3.3.2 The sigmaE Checkpoint 3.3.3 Late Forespore Gene Expression 3.3.4 Late Mother Cell Gene Expression 4 Assembly of the Spore Surface Layers 4.1 Early Events 4.2 Cortex/Coat/Exosporium Connections 4.3 The Mature Spore 4.4 Germination 5 Conservation and Diversity of the Sporulation Programme 6 Gut Feelings 6.1 The Specificity of Sporulation in the Gut 6.2 The Quality Versus Quantity Trade-Off 6.3 The Colonization Versus Dissemination Trade-Off 6.4 Sporulation in Epidemics Strains References Membrane Vesicles of Clostridioides difficile and Other Clostridial Species 1 Introduction to Membrane Vesicles 2 Vesiculogenesis 2.1 Mechanisms in Gram-Positive Bacteria 2.2 Regulation of Vesiculogenesis 2.3 Phage and Antibiotics 3 MV Contents 3.1 Variability in Content 3.2 Virulence Factors 3.3 Fitness Factors 3.4 Nucleic Acids 3.5 Cell Envelope 4 MV Preparation and Quantification 4.1 General Method of Separation, Concentration, and Purification 4.2 Common Quantification Methods 4.3 Clostridial MV Characteristics 5 Potential Functions of C. difficile MVs 5.1 Toxin Secretion 5.2 Horizontal Gene Transfer 5.3 Phage Infection 5.4 Immunogenicity 5.5 Biofilm Formation 6 Concluding Remarks References Non-human Clostridioides difficile Reservoirs and Sources: Animals, Food, Environment 1 Introduction 2 C. difficile in Farm Animals: European Studies 2.1 C. difficile in Pigs and Cattle 2.2 C. difficile in Other Less Commonly Studied Farm Animals in Europe 2.3 Factors Associated with C. difficile Colonization in Farm Animals 2.4 Infection vs. Carriage of C. difficile in Farm Animals 2.5 Farm Animals and Colonization with Different C. difficile PCR Ribotypes 2.6 Antimicrobial Susceptibility of C. difficile Isolates Isolated from Farm Animals 3 C. difficile in Companion Animals in Europe 4 C. difficile in Horses in Europe 5 C. difficile in Wild Animals in Europe 6 Transmissions Between Animals and Environment 7 C. difficile in Food in Europe 7.1 Detection of Contaminated Meats in Retail Markets 7.2 C. difficile in Foods Other than Meats in Europe 8 Studies on C. difficile in Environment in European Countries 9 Importance of Animals, Food, and Environment for Human Infection References The ESCMID Study Group for Clostridioides difficile: History, Role, and Perspectives 1 Introduction 2 The History and Origins of ESGCD 3 Activities and Achievements of ESGCD 3.1 Laboratory Investigation of CDI 3.2 Epidemiology and Surveillance of CDI in Europe 3.3 Management of CDI 4 Current Activities of ESGCD 5 Perspectives and the Future References