Ian R Poxton

The University of Edinburgh | UoE · Edinburgh Infectious Diseases

Background: Bezlotoxumab has been shown to prevent Clostridium difficile infection recurrence (rCDI) in high-risk patients. Methods: We used whole genome sequencing to estimate the impact of bezlotoxumab on same-strain relapse or new-strain reinfection in MODIFY I/II trials. Reinfection with a new strain and relapse with the same strain were dif...

Background: Endogenous antibodies (eAbs) against Clostridioides (Clostridium) difficile toxins may protect against recurrence of C. difficile infection (rCDI). This hypothesis was tested using placebo group data from MODIFY (Monoclonal Antibodies for C. difficile Therapy) I and II (NCT01241552 and NCT01513239, respectively), global, randomized pha...

Clostridium difficile is an important nosocomial pathogen associated with potentially fatal disease induced by the use of antibiotics. Genetic characterisation of such clinically important bacteria is often hampered by availability of suitable tools. Here we describe the use of I-SceI to induce DNA double-strand breaks which increase the frequency...

Background MODIFY I/II were global trials of the efficacy and safety of bezlotoxumab (BEZ), a monoclonal antibody (mAb) against C. difficile toxin B, alone and with actoxumab (ACT), a mAb against C. difficile toxin A. BEZ was superior to placebo (PBO) at preventing recurrent CDI (rCDI) in patients (patients) receiving antibacterials for CDI. The ad...

Background Bezlotoxumab (BEZ) and actoxumab (ACT) are monoclonal antibodies against C. difficile toxins B and A, respectively. Patients receiving a single infusion of BEZ alone or with ACT in the MODIFY I/II trials showed an absolute 10% (relative ~40%) reduction in rCDI over 12-weeks compared with placebo (PBO). The addition of ACT did not improve...

This chapter explores the use of genomics and proteomics to investigate factors responsible for the varying virulence of different Clostridium difficile strains. At first glance, the virulence of C. difficile is a simple process, in that disease is mediated by two large clostridial toxins, toxin A and toxin B. In order to maximize the power of geno...

BACKGROUND Clostridium difficile is the most common cause of infectious diarrhea in hospitalized patients. Recurrences are common after antibiotic therapy. Actoxumab and bezlotoxumab are human monoclonal antibodies against C. difficile toxins A and B, respectively. METHODS We conducted two double-blind, randomized, placebo-controlled, phase 3 trial...

Background Clostridium difficile is the most common cause of infectious diarrhea in hospitalized patients. Recurrences are common after antibiotic therapy. Actoxumab and bezlotoxumab are human monoclonal antibodies against C. difficile toxins A and B, respectively. Methods We conducted two double-blind, randomized, placebo-controlled, phase 3 tria...

Though the molecular aspect of microbiology has long been recognized, it has greatly expanded in recent years. The molecular study of medical microbiology has revealed conceptual insights and technical approaches that have advanced the subject almost beyond recognition. The biological experiments by Fred Griffiths that identified the pneumococcal t...

Teichoic acids and similar molecules can make up 50% of the cell wall of Gram-positive bacteria, and their lipid-linked analogues are bound to the cytoplasmic membrane, expressed on the surface and are essential for viability. Their main function is to bind cations for use by the bacterial cell. They also function as pathogen-associated molecular p...

Reasons for performing study: Equine grass sickness (EGS) is of unknown aetiology. Despite some evidence suggesting that it represents a toxico-infection with Clostridium botulinum types C and/or D, the effect of EGS on the functional targets of botulinum neurotoxins, namely the soluble N-ethylmaleimide-sensitive factor attachment receptor (SNARE)...

Background. Actoxumab ((ACT) MK-3415) and bezlotoxumab ((BEZ) MK- 6072) are human monoclonal antibodies against Clostridium difficile toxins A and B, respectively. Methods. Combined data from 2 double-blind, randomized, phase 3 studies in adult patients receiving oral standard of care (SoC) (metronidazole, vancomycin, or fidaxomi- cin) for primary...

The molecular age has brought about dramatic changes in medical microbiology, and great leaps in our understanding of the mechanisms of infectious disease. Molecular Medical Microbiology is the first book to synthesise the many new developments in both molecular and clinical research in a single comprehensive resource. This timely and authoritative...

Low serum concentrations of antibodies directed against the toxins TcdA and TcdB have been associated with a higher risk of recurrence of Clostridium difficile infection (CDI) after successful antibiotic treatment. However, there are conflicting reports. Herein, we compared serum levels of antibodies of patients with a single episode of CDI with th...

Background Clostridium difficile is an important cause of intestinal infections in some animal species and animals might be a reservoir for community associated human infections. Here we describe a collection of animal associated C. difficile strains from 12 countries based on inclusion criteria of one strain (PCR ribotype) per animal species per l...

This prospective study was performed to determine the incidence, risk factors, severity and outcomes of community-associated Clostridium difficile infection (CA-CDI) in the SE of Scotland. All patients (335) diagnosed with laboratory confirmed CDI in the city of Edinburgh, East Lothian and Midlothian regions of Scotland between August 2010 and July...

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The soluble proteome of three Clostridium difficile strains of varying pathogenic potential designated B-1, Tra 5/5 and 027 SM were compared using Differential In-Gel Electrophoresis (DIGE) in which the proteins of each strain were labelled with CyDyes. This enabled visual inspection of the 2D profiles of strains and identification of differentiall...

JMM E d i t o r i a l Clostridium difficile – special collection The 4th International Clostridium difficile Symposium (ICDS) was held at its traditional location – Bled, Slovenia – from 20 to 22 September 2012. The meeting once more brought together the main individuals and research groups from academia, industry and clinical settings. The number...

Clostridium difficile infection (CDI) has proven to be a constantly evolving disease periodically posing new diagnostic and clinical dilemmas. Different regions of the world have reported specific local genomic characteristics of the infecting strains, which may be related to variation in disease presentation and outcome. Three hundred and thirty-f...

Late in 1978 my boss gave me a folder with "Clostridium difficile (diffikilé)" written on it. Inside were a few recent and now classic papers by Bartlett, Larson and co. It was suggested that this might be an interesting research topic. So began a continuing adventure which has resulted in at least 50 publications from my group. Over the years we h...

Doctors' knowledge provides the basis to support good practice in infection prevention and control. However, there exists a paucity of validated knowledge assessment tools that can be reliably employed to identify poor knowledge levels of Clostridium difficile infection (CDI) within populations of doctors, preventing the effective identification of...

Clostridium difficile is a major cause of nosocomial diarrhoea. The toxins produced by C. difficile are responsible for the characteristic pathology observed in C. difficile disease, but several surface-associated proteins of C. difficile are also recognized by the immune system and could modulate the immune response in infection. The aim of this s...

Strains of Clostridium difficile produce a number of surface-localized proteins, including the S-layer proteins (SLPs) and other proteins that have suspected roles in pathogenesis. During the Third International C. difficile Symposium (Bled, Slovenia, September 2010) discussions were held on standardization of nomenclature. Gene designations were p...

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Clostridium difficile is a common nosocomial pathogen transmitted mainly via its spores. These spores can remain viable on contaminated surfaces for several months and are resistant to most commonly used cleaning agents. Thus, effective decontamination of the environment is essential in preventing the transmission of C. difficile in health-care est...

Clostridium difficile is a major cause of nosocomial diarrhoea. The toxins that it produces (TcdA and TcdB) are responsible for the characteristic pathology of C. difficile infection (CDI), while its spores persist in the environment, causing its widespread transmission. Many different strains of C. difficile exist worldwide and the epidemiology of...

The Ring Ouzel Turdus torquatus is a Red-listed, UK Biodiversity Action Plan priority species in Britain because of steep declines in breeding numbers over the past 25 years. Data from several monitoring projects, from across much of the species' British range, show that widespread declines continue. Recent studies aimed at understanding these decl...

Clin Microbiol Infect 2010; 16: 340–346 Clostridium difficile infection (CDI) is a growing concern with regard to increases in incidence and its associated financial burden. A retrospective analysis of patients admitted to Hospitals in Edinburgh from 2003 to 2007 and tested for C. difficile toxins was performed. A total of 45 412 faecal samples wer...

Clostridium difficile infection is now a major concern throughout the developed world and its occurrence is a consequence of broad-spectrum antibiotic therapy primarily in the elderly in-patient population and high spore loads in hospitals in these regions. With the emergence of a hypervirulent, endemic strain, more severe disease is being recogniz...

ABSTRACT Clostridium difficile infection (CDI) is a growing concern with increases in incidence and associated financial burden. Retrospective analysis of patients admitted to Hospitals in Edinburgh from 2003-2007 and tested for C. difficile toxins was performed. A total of 45412 faecal samples were tested and 6286 (13.8%) were positive. Overall CD...

An increase in the incidence of clinical cases of Clostridium difficile infection has been reported in recent years, but few studies have examined changes in molecular epidemiology and antibiotic resistance over a long period of time. A collection of 179 isolates of C. difficile obtained from symptomatic adult patients in southern Scotland between...

Infections caused by Escherichia coli have an economically significant impact on the poultry industry and a non-serotype-specific vaccine appears to be the most logical method of controlling them. The core oligosaccharide-lipid A region of bacterial lipopolysaccharide (LPS) is well conserved and highly immunogenic but toxic. This study determined t...

Whole gut lavage fluid (WGLF) is an ideal source of gut-derived immunoglobulin for the study of the immune response to the normal bacterial population of the gastrointestinal (GI) tract. An ELISA has been developed for measurement of IgA reacting with cell surface antigens (lipopolysaccharide LPS; and whole outer membrane, OM) of two species of Bac...

Although it is desirable to identify the interactions between endotoxin/LPS and the innate immune mechanism, it is often not possible to isolate these interactions from other cell wall-related structures of protein or polysaccharide origin. There is no universally accepted method to extract different LPSs from different bacteria, and their natural...

Clostridium difficile-associated diarrhoea (CDAD) occurs sporadically or in small discrete outbreaks. Stochastic models may help to inform hospital infection control strategies. Bayesian framework using data augmentation and Markov chain Monte Carlo methods were applied to a spatio-temporal model of CDAD. Model simulations were validated against 17...

Outbreaks of Clostridium difficile infections (CDI) with increased severity, high relapse rate and significant mortality have been related to the emergence of a new, hypervirulent C. difficile strain in North America and Europe. This emerging strain is referred to as PCR ribotype 027 (Type 027). Since 2005, individual countries have developed surve...

Five distinct lipopolysaccharide (LPS) core types, namely R1-R4 and K12 have been identified in Escherichia coli. The aims of this study were to determine, primarily by means of PCR, the distribution of those oligosaccharide core types among avian pathogenic E. coli and their relationship to phylogenetic groups. To identify putative avian pathogeni...

It has been proposed that patients who develop Clostridium difficile-associated disease (CDAD) do so because they are unable to mount an adequate immune response. Serum was collected from three groups of elderly in-patients: (i) cases (n=21) of CDAD, being toxin A/B-positive; (ii) carriers (n=21) asymptomatic for CDAD (no diarrhoea) but at least to...

Cell-surface antigens of Clostridium difficile and LPS from Escherichia coli were investigated for modulating effects on the activity of C. difficile toxin A on Vero and Caco2 cells. The antigens of C. difficile tested comprised: (i) an EDTA extract, which contained several major and minor cell-surface proteins and the membrane-associated lipocarbo...

The European Study Group on Clostridium difficile (ESGCD) conducted a prospective study in 2005 to monitor and characterize C. difficile strains circulating in European hospitals, collecting 411 isolates. Eighty-three of these isolates, showing resistance or intermediate resistance to moxifloxacin (MX), were selected for this study to assess suscep...

A 2-month prospective study of Clostridium difficile infections was conducted in 38 hospitals from 14 different European countries in order to obtain an overview of the phenotypic and genotypic features of clinical isolates of C. difficile during 2005. Of 411 isolates from diarrhoeagenic patients with suspected C. difficile-associated diarrhoea (CD...

There is much evidence to suggest that group III Clostridium botulinum (types C and D) are involved in the aetiology of equine grass sickness (EGS). Antibodies have been detected previously in the blood and high levels associated with resistance to disease. Specific mucosal antibodies in the gastrointestinal (GI) tract are likely to be important in...

Serum from 12 horses suffering from chronic grass sickness (CGS) were assayed for IgG antibodies against botulinum neurotoxins C and D (BoNT/C and BoNT/D) and to a surface antigen extract of a neurotoxin negative strain of Clostridium botulinum type C. Collectively, the six surviving CGS cases demonstrated significantly higher initial IgG levels (P...

Clostridium difficile isolates (n=149) collected in south-east Scotland between August and October 2005 were typed by four different methods and their susceptibility to seven different antibiotics was determined. The aims were to define the types of strain occurring in this region and to determine whether there were any clonal relationships among t...

Recent outbreaks of Clostridium difficile-associated diarrhoea (CDAD) with increased severity, high relapse rate and significant mortality have been related to the emergence of a new, hypervirulent C. difficile strain in North America, Japan and Europe. Definitions have been proposed by the European Centre of Disease Prevention and Control (ECDC) t...

Acinetobacter baumannii is a major nosocomial pathogen and frequent cause of hospital-acquired pneumonia, surgical wound infections and sepsis. As very little is known of the endotoxic potential of A. baumannii lipopolysaccharide (LPS) with respect to human cells or of its ability to stimulate inflammatory signalling via human Toll-like receptors (...

The closely related Clostridium novyi and Clostridium botulinum types C and D are of current interest because of their association with serious infections in injecting drug users (C. novyi type A) and equine and feline dysautonomias (C. botulinum types C/D). The species are defined by the major toxins they produce: the alpha toxin of C. novyi, and...

IntroductionDescription of the Genus ClostridiumPathogenicityGeneral Methods for the Isolation of Clostridium SpeciesClostridium PerfringensClostridium NovyiNeurotoxic ClostridiaClostridium TetaniOther ClostridiaGenomics of ClostridiaSummaryReferences

The identification of Toll-like receptors has revolutionised our understanding of innate immunity. TLR4 transduces the LPS signal and that of a number of structurally and functionally unrelated agonists. However, recent evidence adds to longstanding concerns that endotoxin contamination of bacterially derived recombinant TLR4 agonists is responsibl...

The oral flora is one of the most ecologically diverse microbial populations known to man. It contains at least 350 different cultivable species, with probably a further 50% that cannot be cultured with current laboratory techniques. Saliva contains up to 100 million organisms per millilitre.

The skin provides an excellent defence for the underlying tissues against invading, pathogenic micro-organisms (Chapter 8). The structural elements of normal skin that are important in this protection include its acid pH, the limited amount of moisture present and excreted chemicals such as sebum, fatty acids and urea. In addition, the skin is colo...

The blood-borne viruses (BBVs) comprise a heterogeneous group of viruses, which share a common characteristic of transmission between hosts via blood-to-blood contact. They are very relevant to dentistry, since they pose an occupational hazard for dental personnel, and may also be transmitted to patients from infected dental staff or as a result of...

The central nervous system (CNS) and spinal cord form a distinct body compartment, which depends on migration of white blood cells to and from the blood circulation. The clinical signs and symptoms of infections depend on which area of the CNS is involved, but include altered levels of consciousness, headache, and signs of raised intracranial press...

A bacterial pathogen is simply a bacterium that causes harm to a host, resulting in disease, whilst pathogenicity is the process by which this is brought about. Before describing bacterial pathogenicity, it is useful to consider some of the biological relationships that occur between bacteria and the human body. The body is naturally colonized by a...

This book presents the science of microbiology in a clinical context that is relevant to the safe and effective practice of dental surgery. Microbiology is a rapidly moving discipline. Since the First Edition, a number of infectious diseases such as Creutzfeldt-Jakob Disease and SARS have emerged as significant clinical problems. There have also be...

Most bacteria are either spherical (coccus) or rod-shaped (bacillus), and are usually arranged in a manner characteristic of the genus, growing either singly, in clusters or in chains. The dimensions of a bacterium are typically in the order of 1 μm (Fig. 2.1). As described in the previous chapter, bacteria are typical prokaryotes. Most bacteria ca...

Dental caries can be thought of as a chronic infection of enamel or dentine in which the microbial agents are members of the normal commensal flora. Lesions result from the demineralization of enamel or dentine by acids produced by plaque micro-organisms as they metabolize dietary carbohydrates. Once the surface layer of enamel has been lost, the i...

Genes are the elements of the hereditary material of living cells that carry the information to code for all the necessary components and reactions of life. At cell division the genes are replicated and a copy goes to each daughter cell. It was not until the 1950s that deoxyribonucleic acid (DNA) was recognized as being the substance of genes. Duri...

Periodontal disease in its widest sense includes all disorders of the supporting structures of the teeth, namely the gingiva, periodontal ligament and supporting alveolar bone. This may vary from inflammation of the gingiva alone, termed gingivitis (Fig. 24.1), to the severe inflammation of the periodontal ligament called periodontitis (Fig. 24.2),...

Taxonomy is the term given to the systematic classification, naming, and identification of living organisms. Bacterial taxonomy is often thought of as a complex but ‘necessary evil’, that is uninteresting to learn and overwhelms many students. It is, however, at the very root of biological communication and is essential for describing an organism,...

The introduction of immunization against infectious disease has been one of the most successful developments in medicine. It was pioneered at the end of the eighteenth century by Edward Jenner to prevent smallpox and due to the remarkable success of world-wide vaccination programmes in the latter half of the twentieth century, the disease has been...

The general aspects of host defences have already been described in Chapter 8. In this short chapter, attention will be drawn to some of the specific aspects relating to immunity in the mouth. The key factors responsible for maintaining oral health are listed in Fig. 22.1. Oral health is dependent on the integrity of the oral mucosa, which normally...

Infective endocarditis was first recognised in 1885 by Sir William Osler, who described the clinical appearance as ‘malignant endocarditis’, because of the rapid progress of the disease and multisystem involvement. Osler also described the valvular defects of endocarditis as vegetations and noted that ‘micrococci are constant elements in the vegeta...

Accurate diagnosis of infections is essential if they are to be treated appropriately. The main aims of a diagnostic microbiology laboratory are to identify any causative organisms and to provide guidance on appropriate antimicrobial therapy. Antimicrobial sensitivity testing has already been discussed in Chapter 10. In the present chapter, the wid...

Fungal infections in the oral and perioral regions occur either as primary localized lesions or as manifestations of systemic mycoses. By far the most common group of fungal infections that dental practitioners diagnose and treat are caused by Candida spp.. Some of the rarer mycoses with oral manifestations, such as histoplasmosis, are found almost...

The management of infection is an important element of clinical dentistry, and antimicobial drugs frequently play a role in the treatment of both purulent and mucosal infections in the head and neck region. Antimicrobial agents may also be used prophylactically, for example in the prevention of infective endocarditis among susceptible patients rece...

The inappropriate prescribing of antimicrobial drugs through incorrect diagnoses, choice of agent, dose and duration of treatment contributes to the increasing development of antimicrobial resistance, both in pathogens and members of the commensal flora. There is substantial evidence to suggest that dental practitioners, in common with many other h...

As discussed in previous chapters, bacteria are responsible for both dental caries and periodontal diseases. Extension of these diseases commonly causes infection in the adjacent tissues, notably the pulp, periapical area and oro-facial soft tissues. More rarely, infection may become established in the bone of the jaw to cause osteomyelitis. These...

In this chapter gastrointestinal infections are defined as diseases caused by micro-organisms which affect the stomach, small intestine, or large intestine and are usually characterized by the symptoms of vomiting and/or diarrhoea. The acquisition of the infecting agent is usually either via the faecal–oral route or through consuming contaminated f...

There are over 100 identified herpes viruses in nature. The hostspan includes vertebrates and invertebrates, but the viruses share common structural and genomic properties. All are icosahedral viral particles (Fig. 6.2, p. 56) 150–200 nm in diameter made up of 162 hollow capsomeres, and possess a double-stranded DNA genome. Herpes viruses all have...

Specific bacterial infections of the oral mucosa are uncommon in the USA and Europe and many are manifestations of systemic diseases, for example syphilis, gonorrhoea or tuberculosis. Such infections are seen more frequently in many developing countries. The microbiology of this sexually transmitted disease, caused by Neisseria gonorrhoeae (N. gono...

Infection control is a critical element of safe dental practice. In recent years there has been heightened professional and public awareness of the potential for cross-infection in the dental surgery. The emergence of human immunodeficiency virus (HIV) in the early 1980s prompted a major review of infection control procedures in dentistry. In line...