DOCSLIB.ORG

Factors Affecting the Detection of Clostridium Difficile in Faecal Samples

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Factors Affecting the Detection of Clostridium Difficile in Faecal Samples 1 Factors affecting the detection of Clostridium difficile in faecal samples Kerrie Ann Davies Submitted in accordance with the requirements for the degree of Doctor of Philosophy The University of Leeds School of Medicine April 2019 2 The candidate confirms that the work submitted is her own, except where work which has formed part of jointly authored publications has been included. The contribution of the candidate and the other authors to this work has been explicitly indicated below. The candidate confirms that appropriate credit has been given within the thesis where reference has been made to the work of others. Section 6.2.1 of Chapter 4 contains work from a jointly authored publication; Davies K, Planche T and Wilcox M. The predictive value of quantitative nucleic acid amplification detection of Clostridium difficile toxin gene for faecal sample toxin status and patient outcome. PLoS One 13(12): e0205941 2018. The concept of the work was devised by Kerrie Davies, the analysis and initial draft of the manuscript was completed by Kerrie Davies with review by Dr Tim Planche and Prof Mark Wilcox. This copy has been supplied on the understanding that it is copyright material and that no quotation from the thesis may be published without proper acknowledgement. The right of Kerrie Davies to be identified as Author of this work has been asserted by Kerrie Davies in accordance with the Copyright, designs and Patents Act 1988. 3 Acknowledgements There are so many people who I need to thank for their part in helping me to achieve this thesis. The Department of Health study, for which I was scientific coordinator, was conducted prior to this PhD, but I have reused the data for further analysis within the thesis. I would therefore like to thank all of the sites that took part in the multi-centre study; Leeds Teaching Hospitals NHS trust, St Georges’ University Hospitals NHS Foundation Trust, UCL Hospitals NHS Foundation Trust and Oxford University Hospitals NHS Foundation Trust, with special thanks to Dr Tim Planche for all of his support and guidance. I would also like to thank the Department of Health, who funded both this initial study and the PlaciD study. The PlaciD study research was carried out by a team which has included Claire Berry (Clinical Scientist), Claire Brown (Research Nurse) and Faye Pinker (Research Nurse). My own contributions, fully and explicitly indicated in the thesis, for the PlaciD study were to devise the study, be study chief investigator, write the study protocol, apply for ethical approval, devise data collection sheets and databases, perform the majority of the laboratory testing of the samples and analyse the data. The other members of the team and their contributions have been as follows; The Research Nurses recruited all of the participants, collected their samples and their data; Claire Berry performed laboratory testing of the samples during my maternity leave (four months). Thanks go to all of the team. I would also like to thank all of the participants in the PlaciD study, who generously gave their time, and poo, to help make the study a success! The gut models require a huge team effort to keep them running, therefore the research using this system has been carried out by a team which has included; Dr Tony Buckley (PI), Dr Caroline Chilton (PI), Dr Ines Moura (research assistant), Dr Hannah Harris (research assistant), Duncan Ewin (technician), Sharie Shearman (technician), Emma Clarke (technician), Kate Owens (technician), Bill Spittal (senior technician) and Flor Sporta (Summer student). My own contributions, fully and explicitly indicated in the thesis, have been to devise the experiments using gut model samples to monitor proliferation of C. difficile within the gut models using commercial assays, to test the samples, except where tested by Flor Sporta, as detailed within the thesis, and analyse the data. The other members of the team and their contributions have been as follows; individual gut model experiments devised and overseen by the PI in each case; all the technical aspects of keeping the gut models running was completed by the technical team (technicians and 4 research assistants), including taking the daily samples; Flor Sporta tested some of the gut model samples using the DS2 assays, as explicitly indicated in the thesis. I would like to thank each and every one of them for their assistance. All PCR ribotyping was carried out by the C. difficile Ribotyping Network of England and Northern Ireland (CDRN), as explicitly stated within the thesis. I would like to thank Dr Warren Fawley and his team at CDRN for their contribution and support. The Healthcare Associated Infections Research Group is a special place to work and I feel very privileged to be part of such a great team. Every single person deserves my thanks, but I’d especially like to thank Dr Jane Freeman, for being my ever steady friend who always steers me right; Dr Baljit Saundh, my dear friend who helps me to ‘relax the chaos’; Georgina Davis, my great friend and dedicated cheering squad, who never lets me quit; and of course Prof Mark Wilcox, my PhD Supervisor and mentor, who has given me the opportunity to fly. A great debt of thanks also goes to Dr John Heritage; not only is he the reason I came to Leeds to study Microbiology as an undergraduate, but he was also my PhD co-supervisor, even after he had retired. I appreciate all of the wisdom and advice he has imparted over the many years I have known him. Huge thanks go to my family; for standing by me, for keeping me encouraged and inspired. To my children Alf and Sid, for being patient when I couldn’t play, and for making me laugh whenever they could; to my mum and dad for being so supportive and proud; to my extended Leeds family for supporting us all and providing ‘donations’ when needed. Special thanks obviously go to Graeme, my amazing husband; without him this thesis, my career and my self-belief would be naught. This PhD thesis is dedicated to my dad; for inspiring me to be the scientist that he never got the chance to be. 5 Abstract Clostridium difficile infection (CDI) laboratory diagnostic assays have variable performance, but reasons behind this variability are not well defined. In contrast to previous findings, the PCR ribotype of the organism only appears to be a factor in reduced sensitivity for toxin enzyme immunoassays (EIAs), not glutamate dehydrogenase (GDH) EIAs. Growth curve data demonstrated that GDH is produced during the exponential phase of growth, and the sensitivity of the GDH assay in vivo may be related to the amount of protein produced by the organism, as very high levels of GDH were detected during growth of C. difficile in an in vitro gut model. Indeed the levels of GDH, measured in both gut model and patient samples, correlated with organism bioload. In addition, the median faecal levels of GDH in recurrent CDI cases were significantly higher than in patients with a single infection episode. Interestingly, when patients had sequential faecal samples tested, 27% with an initial GDH- positive/toxin-negative result had a subsequent toxin positive sample, after a median of eight days. Further studies, with supplementary assays for gut inflammation, are required, to determine if these are ‘missed’ infections or insignificant sub-clinical levels of toxin. A laboratory test that could predict risk of recurrence would be an important tool to inform choice of appropriate C. difficile treatment and prevention options. Indeed GDH detection may offer such an opportunity; a cohort of patients has been identified who were consistently GDH positive, even after resolution of symptoms, who subsequently developed recurrent CDI following additional antimicrobial therapy. The cycle threshold (CT) value of PCR assays for the detection of toxin gene may also provide additional information, as low CT (<25) was significantly associated with toxin positivity, presence of PCR ribotype 027 and mortality. Low CT was also associated with recurrence but was not a significant finding. 6 Contents Acknowledgements .............................................................................................................. 3 Abstract ................................................................................................................................ 5 List of Tables ...................................................................................................................... 11 List of Figures ..................................................................................................................... 14 Abbreviations used in this thesis ....................................................................................... 19 1.0 Introduction ................................................................................................................. 21 1.1 Historical context ..................................................................................................... 21 1.2 Virulence factors ...................................................................................................... 22 1.2.1 Toxins ................................................................................................................ 22 1.2.2 Spores ................................................................................................................ 24 1.2.3 Other Virulence Factors .................................................................................... 25 1.3 Clinical manifestations ............................................................................................
Load more

Recommended publications
  • Antimicrobial Resistance in Companion Animal Pathogens in Australia and Assessment of Pradofloxacin on the Gut Microbiota
    Antimicrobial resistance in companion animal pathogens in Australia and assessment of pradofloxacin on the gut microbiota Sugiyono Saputra A thesis submitted in fulfilment of the requirements of the degree of Doctor of Philosophy School of Animal and Veterinary Sciences The University of Adelaide February 2018 Table of Contents Thesis Declaration ...................................................................................................................... iii Dedication ................................................................................................................................. iv Acknowledgement ...................................................................................................................... v Preamble .................................................................................................................................... vi List of Publications ..................................................................................................................... vii Abstract .......................................................................................................................................ix Chapter 1 General Introduction ................................................................................................. 1 1.1. Antimicrobials and their consequences ............................................................................ 2 1.2. The emergence and monitoring AMR................................................................................ 2
    [Show full text]
  • Revisión Bibliográfica
    Vol. 34 (1), Marzo 2017. ISSN 1409-0015 Medicina Legal de Costa Rica - Edición Virtual REVISIÓN BIBLIOGRÁFICA Antibioticoterapia y nuevas terapias no farmacológicas en infecciones por Clostridium difficile Barrientos Jiménez, Maryam1; Esquivel Zúñiga, María Rebeca2; 3 4 5 Álvarez Umaña Silvia Vanessa ; Tencio Araya, Jose ; Soto Cerdas Jahaira Resumen: La infección por Clostridium difficile es la principal causa de diarrea infecciosa en pacientes hospitalizados. Los pacientes pueden ser portadores asintomáticos o presentar desde una diarrea leve a una colitis pseudomembranosa, megacolon tóxico, sepsis y muerte. El manejo de esta infección sigue presentando puntos de controversia, tanto en la elección del mejor método diagnóstico como en el tratamiento. En los casos en los cuales la infección por este agente fue confirmada la primera y más efectiva medida es suspender la antibioticoterapia que el paciente este recibiendo, en la medida de lo posible. El tratamiento se basa en tres agentes clásicos: metronidazol, vancomicina y teicoplanina con la más reciente adición de fidaxomicina y ridinilazol. Pacientes con presentación severa muchas veces requieren resolución quirúrgica además de las medidas de soporte y monitoreo. El objetivo de esta revisión es ofrecer información actualizada sobre la patogénesis y estrategias terapéuticas sobre el manejo de la infección por este patógeno. Palabras claves: Clostridium difficile, infección por Clostridium difficile, colitis pseudomembranosa. Fuente: MeSH Abstract: Clostridium difficile infection is the leading cause of hospital acquired diarrhea. The patients can be asymptomatic carriers or present a mild diarrhea, a pseudomembranous colitis, toxic megacolon, sepsis and death. There is controversy in this infection’s including the best method of diagnosis and also regarding therapeutic regimen.
    [Show full text]
  • Ridinilazole: a Novel Antimicrobial for Clostridium Difficile Infection
    REVIEW ARTICLE Annals of Gastroenterology (2019) 32, 134-140 Ridinilazole: a novel antimicrobial for Clostridium difficile infection Jonathan C. Choa, Matthew P. Crottyb, Joe Pardoc The University of Texas at Tyler, Tyler, TX; Methodist Dallas Medical Center, Dallas, TX; North FL/South GA Veterans Health System, Gainesville, FL, USA Abstract Clostridium difficile (C. difficile) infection remains a global healthcare threat worldwide and the limited options available for its treatment are of particular concern. Ridinilazole is one potential future agent, as it demonstrates rapid bactericidal activity against C. difficile. Current studies show that ridinilazole has a lower propensity for collateral damage to the gut microbiome and appears to diminish the production of C. difficile toxins. Results from phase II studies demonstrate that patients receiving ridinilazole had a higher sustained clinical response compared with patients receiving vancomycin (66.7% vs. 42.4%; P=0.0004). Adverse reactions were similar between ridinilazole and vancomycin (40% vs. 56%, respectively), with most being gastrointestinal-related. Nausea (20%) and abdominal pain (12%) were the most commonly reported adverse reactions associated with ridinilazole. Phase II study results are promising and future availability of phase III trial results will help further delineate the role and value of ridinilazole. Keywords Ridinilazole, Clostridium difficile, infectious diarrhea Ann Gastroenterol 2019; 32 (2): 134-140 Introduction aspects of managing patients with C. difficile is the pathogen’s propensity to cause recurrent infections. Recurrence rates Clostridium difficile (C. difficile) is recognized as an urgent of up to 25% have been reported following treatment with metronidazole or vancomycin [14,15]. The vicious cycle of threat to human health and represents an extremely challenging recurrence continues further, with patients who have one pathogen, given its impact on the healthcare system [1-5].
    [Show full text]
  • Ridinilazole—A Novel Antibiotic for Treatment of Clostridium Difficile Infection
    120 Editorial Ridinilazole—a novel antibiotic for treatment of Clostridium difficile infection Niels Steinebrunner, Wolfgang Stremmel, Karl H. Weiss Department of Gastroenterology and Hepatology, University Hospital Heidelberg, Heidelberg, Germany Correspondence to: Prof. Karl Heinz Weiss, MD. Department of Gastroenterology and Hepatology, University Hospital Heidelberg, Heidelberg 69120, Germany. Email: [email protected]. Provenance: This is an invited Editorial commissioned by Section Editor Dr. Ming Zhong (Department of Critical Care Medicine, Zhongshan Hospital, Fudan University, Shanghai, China). Comment on: Vickers RJ, Tillotson GS, Nathan R, et al. Efficacy and safety of ridinilazole compared with vancomycin for the treatment of Clostridium difficile infection: a phase 2, randomised, double-blind, active-controlled, non-inferiority study. Lancet Infect Dis 2017;17:735-44. Submitted Dec 04, 2017. Accepted for publication Dec 18, 2017. doi: 10.21037/jtd.2017.12.117 View this article at: http://dx.doi.org/10.21037/jtd.2017.12.117 Clostridium difficile (C. difficile) infection has become a major completing initial therapy. Risk factors for recurrence of health problem worldwide and is considered to be one of CDI include gastric acid suppression by proton pump the most common hospital-acquired (nosocomial) infections inhibitor therapy, gastrointestinal tract surgery, underlying with increasing incidence and severity (1). In Germany, immunosuppression (malignancy, cirrhosis, chemotherapy, the number of C. difficile infections (CDI) increased from immunosuppressive therapy), as well as older age 7 to 39 reported cases per 100,000 hospitalized patients (>65 years) of affected patients (6-11). Recurrent infections between 2000 and 2004, with yet another doubling of are associated with an increased risk of further episodes of numbers between 2004 and 2006 (2).
    [Show full text]
  • IX Updating Course of Antimicrobials and Infectious Diseases
    REVISTA ESPAÑOLA DE QQuimioterapiauimioterapia SPANISH JOURNAL OF CHEMOTHERAPY ISSN: 0214-3429 Volume 32 Supplement number 2 September 2019 Pages: 01-79 IX Updating Course of Antimicrobials and Infectious Diseases Coordination: Dr. FJ. Candel González Servicio de Microbiologia Clínica Hospital Clínico San Carlos Madrid. Spain. 18 y 19 de febrero de 2019 Auditorio San Carlos. Pabellón Docente Publicación Oficial Hospital Clínico San Carlos de la Sociedad Española de Quimioterapia REVISTA ESPAÑOLA DE Quimioterapia Revista Española de Quimioterapia tiene un carácter multidisciplinar y está dirigida a todos aquellos profesionales involucrados en la epidemiología, diagnóstico, clínica y tratamiento de las enfermedades infecciosas Fundada en 1988 por la Sociedad Española de Quimioterapia Sociedad Española de Quimioterapia Indexada en Publicidad y Suscripciones Publicación que cumple los requisitos de Science Citation Index Sociedad Española de Quimioterapia soporte válido Expanded (SCI), Dpto. de Microbiología Index Medicus (MEDLINE), Facultad de Medicina ISSN Excerpta Medica/EMBASE, Avda. Complutense, s/n 0214-3429 Índice Médico Español (IME), 28040 Madrid Índice Bibliográfico en Ciencias e-ISSN de la Salud (IBECS) 1988-9518 Atención al cliente Depósito Legal Secretaría técnica Teléfono 91 394 15 12 M-32320-2012 Dpto. de Microbiología Correo electrónico Facultad de Medicina [email protected] Maquetación Avda. Complutense, s/n Kumisai 28040 Madrid [email protected] Consulte nuestra página web Impresión Disponible en Internet: www.seq.es España www.seq.es Esta publicación se imprime en papel no ácido. This publication is printed in acid free paper. LOPD Informamos a los lectores que, según lo previsto © Copyright 2019 en el Reglamento General de Protección Sociedad Española de de Datos (RGPD) 2016/679 del Parlamento Quimioterapia Europeo, sus datos personales forman parte de la base de datos de la Sociedad Española de Reservados todos los derechos.
    [Show full text]
  • C. Difficile: Trials, Treatments and New Guidelines
    C. difficile: trials, treatments and new guidelines CONTENTS REVIEW: Vulnerability of long-term care facility residents to Clostridium difficile infection due to microbiome disruptions FUTURE MICROBIOLOGY Vol. 13, No. 13 INTERVIEW: The gut microbiome and the potentials of probiotics: an interview with Simon Gaisford FUTURE MICROBIOLOGY Vol. 14, No. 4 REVIEW: Clostridioides (Clostridium) difficile infection: current and alternative therapeutic strategies FUTURE MICROBIOLOGY Vol. 13, No. 4 EDITORIAL: Microbiome therapeutics – the pipeline for C. difficile infection INTERVIEW: Updates on C. difficile: from clinical trials and guidelines – an interview with Yoav Golan NEWS ARTICLE: Could common painkillers promote C. difficile infection? Review For reprint orders, please contact: [email protected] Vulnerability of long-term care facility residents to Clostridium difficile infection due to microbiome disruptions Beth Burgwyn Fuchs*,1, Nagendran Tharmalingam1 & Eleftherios Mylonakis**,1 1Rhode Island Hospital, Alpert Medical School & Brown University, Providence, Rhode Island 02903 *Author for correspondence: Tel.: +401 444 7309; Fax: +401 606 5624; Helen [email protected]; **Author for correspondence: Tel.: +401 444 7845; Fax: +401 444 8179; [email protected] Aging presents a significant risk factor for Clostridium difficile infection (CDI). A disproportionate number of CDIs affect individuals in long-term care facilities compared with the general population, likely due to the vulnerable nature of the residents and shared environment. Review of the literature cites a number of underlying medical conditions such as the use of antibiotics, proton pump inhibitors, chemotherapy, renal disease and feeding tubes as risk factors. These conditions alter the intestinal environment through direct bacterial killing, changes to pH that influence bacterial stabilities or growth, or influence nutrient availability that direct population profiles.
    [Show full text]
  • Clostridioides Difficile Infection: a Comprehensive Review for Primary Providers
    Clostridioides difficile infection: a comprehensive review for primary providers PEDRO CORTÉS1, YAN BI2, FERNANDO STANCAMPIANO1, JOSE R. VALERY1, JANE H. COOPER1, DANA M. HARRIS1 1 Division of Community Internal Medicine, Mayo Clinic, Jacksonville, FL, 32224 2 Division of Gastroenterology and Hepatology, Mayo Clinic, Jacksonville, FL, 32224 Clostridioides difficile infection (CDI) is an issue of great concern due to its rising incidence, recurrence, morbidity and impact on healthcare spending. Treatment guidelines have changed in the last few years, and new therapies are being considered. This is a practical review for the primary care practitioner of the latest guidelines for CDI diagnosis, treatment, and emerging therapies. Key words: Clostridioides difficile, eradication, recurrent infection, fecal microbiota transplantation. Abbreviations: CD: Clostridioides Difficile, C. difficile; CDI: Clostridioides Difficile infection ; CDI: recurrent Clostridioides Difficile infection ; FMT: Fecal microbiota transplantation ; GDH: Glutamate dehydrogenase; NAAT: Nucleic acid amplification test. INTRODUCTION treatment of initial CDI, remained unchanged [5]. Notably, up to 25% of patients experience rCDI Clostridioides difficile (CD) was discovered within 30 days of initial treatment [6]. in 1978 and identified as the main etiology Antibiotic usage is the most critical risk of antibiotic-associated pseudomembranous factor for acquisition of CDI [7–9] but advanced colitis [1]; it was known as Clostridium difficile age, hospitalization, and severe comorbid until 2016 when it was reclassified based illness play a role as well [9]. Additional risk on molecular information as Clostridioides factors include enteral feeding [10], difficile [2]. CD is a gram-positive, toxin- inflammatory bowel disease [11], cirrhosis producing anaerobic bacterium, that causes an [12] and gastric acid suppression [9].
    [Show full text]
  • Ridinilazole: a Novel Therapy for Clostridium Difficile Infection Richard J
    International Journal of Antimicrobial Agents 48 (2016) 137–143 Contents lists available at ScienceDirect International Journal of Antimicrobial Agents journal homepage: www.elsevier.com/locate/ijantimicag Review Ridinilazole: a novel therapy for Clostridium difficile infection Richard J. Vickers a,*, Glenn Tillotson b, Ellie J.C. Goldstein c,d, Diane M. Citron c, Kevin W. Garey e, Mark H. Wilcox f a Summit Therapeutics plc, 85b Park Drive, Milton Park, Abingdon, Oxford OX14 4RY, UK b Cempra Pharmaceuticals, Chapel Hill, NC, USA c R.M. Alden Research Laboratory, Culver City, CA, USA d David Geffen School of Medicine at UCLA, Los Angeles, CA, USA e University of Houston College of Pharmacy, Houston, TX, USA f Microbiology, Leeds Teaching Hospitals and University of Leeds, Old Medical School, Leeds General Infirmary, Leeds, UK ARTICLE INFO ABSTRACT Article history: Clostridium difficile infection (CDI) is the leading cause of infectious healthcare-associated diarrhoea. Re- Received 23 March 2016 current CDI increases disease morbidity and mortality, posing a high burden to patients and a growing Accepted 23 April 2016 economic burden to the healthcare system. Thus, there exists a significant unmet and increasing medical need for new therapies for CDI. This review aims to provide a concise summary of CDI in general and a Keywords: specific update on ridinilazole (formerly SMT19969), a novel antibacterial currently under develop- Ridinilazole ment for the treatment of CDI. Owing to its highly targeted spectrum of activity and ability to spare the SMT19969 normal gut microbiota, ridinilazole provides significant advantages over metronidazole and vancomy- Clostridium difficile infection Antibacterial therapy cin, the mainstay antibiotics for CDI.
    [Show full text]
  • CHEMICAL SPACE EXPLORATION AROUND THIENO[3,2-D]PYRIMIDIN-4(3H)-ONE SCAFFOLD LED to a NOVEL CLASS of HIGHLY ACTIVE CLOSTRIDIUM DIFFICILE INHIBITORS
    St. John's University St. John's Scholar Theses and Dissertations 2020 CHEMICAL SPACE EXPLORATION AROUND THIENO[3,2-d]PYRIMIDIN-4(3H)-ONE SCAFFOLD LED TO A NOVEL CLASS OF HIGHLY ACTIVE CLOSTRIDIUM DIFFICILE INHIBITORS Xuwei Shao Follow this and additional works at: https://scholar.stjohns.edu/theses_dissertations Part of the Pharmacy and Pharmaceutical Sciences Commons CHEMICAL SPACE EXPLORATION AROUND THIENO[3,2-d]PYRIMIDIN- 4(3H)-ONE SCAFFOLD LED TO A NOVEL CLASS OF HIGHLY ACTIVE CLOSTRIDIUM DIFFICILE INHIBITORS A dissertation submitted in partial fulfillment of the requirements for the degree of DOCTOR OF PHILOSOPHY to the faculty of the DEPARTMENT OF GRADUATE DIVISION of COLLEGE OF PHARMACY AND HEALTH SCIENCES at St. JOHN’S UNIVERSITY New York by Xuwei Shao Date Submitted: Date Approved: __________________________ ___________________________ Xuwei Shao Dr. Tanaji T. Talele ã Copyright by Xuwei Shao 2020 All Rights Reserved ABSTRACT CHEMICAL SPACE EXPLORATION AROUND THIENO[3,2-d]PYRIMIDIN- 4(3H)-ONE SCAFFOLD LED TO A NOVEL CLASS OF HIGHLY ACTIVE CLOSTRIDIUM DIFFICILE INHIBITORS Xuwei Shao Clostridium difficile infection (CDI) is the leading cause of healthcare-associated infection in the United States. Therefore, development of novel treatments for CDI is a high priority. Toward this goal, we began in vitro screening of a structurally diverse in- house library of 67 compounds against two pathogenic C. difficile strains (ATCC BAA 1870 and ATCC 43255), which yielded a hit compound, 2-methyl-8-nitroquinazolin- 4(3H)-one (2) with moderate potency (MIC = 312/156 µM). Optimization of 2 gave lead compound 6a (2-methyl-7-nitrothieno[3,2-d]pyrimidin-4(3H)-one) with improved potency (MIC = 19/38 µM), selectivity over normal gut microflora, CC50s >606 µM against mammalian cell lines, and acceptable stability in simulated gastric and intestinal fluid.
    [Show full text]
  • Clostridium Difficile
    Colon ORIGINAL ARTICLE Gut: first published as 10.1136/gutjnl-2018-316794 on 25 September 2018. Downloaded from Follow-on RifAximin for the Prevention of recurrence following standard treatment of Infection with Clostridium Difficile (RAPID): a randomised placebo controlled trial Giles Major, 1 Lucy Bradshaw,2 Nafisa Boota,3 Kirsty Sprange,2 Mathew Diggle,4 Alan Montgomery,2 Aida Jawhari,4 Robin C Spiller, 1 on behalf of RAPID Collaboration Group ► Additional material is ABSTRact published online only. To view Background Clostridium difficile infection (CDI) recurs Significance of this study please visit the journal online after initial treatment in approximately one in four (http:// dx. doi. org/ 10. 1136/ What is already known on this subject? gutjnl- 2018- 316794). patients. A single-centre pilot study suggested that this could be reduced using ’follow-on’ rifaximin treatment. ► Recurrence after successful treatment of 1Nottingham Digestive Diseases We aimed to assess the efficacy of rifaximin treatment in Clostridium difficile infection (CDI) occurs in Centre and NIHR Nottingham approximately one in four patients. Biomedical Research Centre at preventing recurrence. Nottingham University Hospitals Methods A multisite, parallel group, randomised, ► Patients are typically frail with multiple NHS Trust, the University of placebo controlled trial recruiting patients aged ≥18 comorbidities. Nottingham, Nottingham, years immediately after resolution of CDI through ► A pilot study suggested that a course of Notts, UK rifaximin after successful treatment might 2Nottingham Clinical Trials treatment with metronidazole or vancomycin. Unit (NCTU), University of Participants received either rifaximin 400 mg three times reduce recurrence by around 50%. Nottingham, Nottingham, UK a day for 2 weeks, reduced to 200 mg three times a day 3 What are the new findings? Leicester Clinical Trials Unit, for a further 2 weeks or identical placebo.
    [Show full text]
  • From Fecal Microbiota Transplantation to Probiotics to Microbiota-Preserving Antimicrobial Agents
    pathogens Review Application of Microbiome Management in Therapy for Clostridioides difficile Infections: From Fecal Microbiota Transplantation to Probiotics to Microbiota-Preserving Antimicrobial Agents Chun-Wei Chiu 1, Pei-Jane Tsai 2, Ching-Chi Lee 3,4 , Wen-Chien Ko 4,5,* and Yuan-Pin Hung 1,4,5,* 1 Department of Internal Medicine, Tainan Hospital, Ministry of Health and Welfare, Tainan 700, Taiwan; [email protected] 2 Department of Medical Laboratory Science and Biotechnology, National Cheng Kung University, Medical College, Tainan 704, Taiwan; [email protected] 3 Clinical Medicine Research Center, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan 704, Taiwan; [email protected] 4 Department of Internal Medicine, College of Medicine, National Cheng Kung University Hospital, Tainan 704, Taiwan 5 Department of Medicine, College of Medicine, National Cheng Kung University, Tainan 704, Taiwan * Correspondence: [email protected] (W.-C.K.); [email protected] (Y.-P.H.) Abstract: Oral vancomycin and metronidazole, though they are the therapeutic choice for Clostrid- Citation: Chiu, C.-W.; Tsai, P.-J.; Lee, ioides difficile infections (CDIs), also markedly disturb microbiota, leading to a prolonged loss of C.-C.; Ko, W.-C.; Hung, Y.-P. colonization resistance to C. difficile after therapy; as a result, their use is associated with a high Application of Microbiome treatment failure rate and high recurrent rate. An alternative for CDIs therapy contains the delivery Management in Therapy for of beneficial (probiotic) microorganisms into the intestinal tract to restore the microbial balance. Clostridioides difficile Infections: From Fecal Microbiota Transplantation to Recently, mixture regimens containing Lactobacillus species, Saccharomyces boulardii, or Clostridium Probiotics to Microbiota-Preserving butyricum have been extensively studied for the prophylaxis of CDIs.
    [Show full text]
  • Impact on Toxin Production and Cell Morphology in Clostridium Difficile by Ridinilazole (SMT19969), a Novel Treatment for C
    J Antimicrob Chemother 2016; 71: 1245–1251 doi:10.1093/jac/dkv498 Advance Access publication 18 February 2016 Impact on toxin production and cell morphology in Clostridium difficile by ridinilazole (SMT19969), a novel treatment for C. difficile infection Euge´nie Basse`res1†, Bradley T. Endres1†, Mohammed Khaleduzzaman1, Faranak Miraftabi1, M. Jahangir Alam1, Richard J. Vickers2 and Kevin W. Garey1* 1University of Houston College of Pharmacy, 1441 Moursund Street, Houston, TX 77030, USA; 2Summit Therapeutics, 85b Park Drive, Milton Park, Abingdon, Oxfordshire OX14 4RY, UK *Corresponding author. E-mail: [email protected] †These authors contributed equally to this work. Received 20 October 2015; returned 26 November 2015; revised 15 December 2015; accepted 21 December 2015 Objectives: Ridinilazole (SMT19969) is a narrow-spectrum, non-absorbable antimicrobial with activity against Clostridium difficile undergoing clinical trials. The purpose of this study was to assess the pharmacological activity of ridinilazole and assess the effects on cell morphology. Methods: Antibiotic killing curves were performed using the epidemic C. difficile ribotype 027 strain, R20291, using supra-MIC (4×and 40×) and sub-MIC (0.125×, 0.25×and 0.5×) concentrations of ridinilazole. Following exposure, C. difficile cells were collected for cfu counts, toxin A and B production, and morphological changes using scan- ning electron and fluorescence microscopy. Human intestinal cells (Caco-2) were co-incubated with ridinilazole- treated C. difficile growth medium to determine the effects on host inflammatory response (IL-8). Results: Treatment at supra-MIC concentrations (4× and 40× MIC) of ridinilazole resulted in a significant reduc- tion in vegetative cells over 72 h (4 log difference, P,0.01) compared with controls without inducing spore formation.
    [Show full text]