#Antibodies to #Toxin B Are Protective Against #Clostridium difficile Infection Recurrence (Clin Infect Dis., abstract)

[Source: Clinical Infectious Diseases, full page: (LINK). Abstract, edited.]

Antibodies to Toxin B Are Protective Against Clostridium difficile Infection Recurrence

Swati B. Gupta1, Vinay Mehta2, Erik R. Dubberke3, Xuemei Zhao4, Mary Beth Dorr5, Dalya Guris5, Deborah Molrine6,7, Mark Leney7,8, Mark Miller9, Marilyne Dupin10, and T. Christopher Mast2

Author Affiliations: 1Public Health and Scientific Affairs  – 2Pharmacoepidemiology, Merck & Co, Inc, Kenilworth, New Jersey  – 3Division of Infectious Diseases, Washington University School of Medicine, St Louis, Missouri  – 4Translational Molecular Biomarkers  – 5Clinical Research, Merck & Co, Inc, Kenilworth, New Jersey  – 6Department of Pediatrics, University of Massachusetts Medical School, Worcester
7MassBiologics, Boston  – 8Department of Medicine, University of Massachusetts Medical School, Worcester  – 9Office of Medical and Scientific Affairs  – 10Medical Diagnostics Discovery Department, bioMérieux, Marcy L’Etoile, France

Correspondence: S. B. Gupta, Merck & Co, Inc., 770 Sumneytown Pike, West Point, PA 19486 (swati.gupta5@merck.com).

 

Abstract

Background. 

Although newer studies have evaluated risk factors for recurrent Clostridium difficile infection (CDI), the vast majority did not measure important biomarkers such as endogenous anti–toxin A and anti–toxin B antibody levels.

Methods. 

Data from the placebo group of a phase 2 trial testing monoclonal antibodies to C. difficile toxins A and B for preventing CDI recurrence (rCDI) were analyzed to assess risk factors associated with rCDI. Patients with symptomatic CDI taking metronidazole or vancomycin were enrolled. The primary outcome was rCDI within 84 days of treatment start. Univariate and multivariate logistic regression was used to examine associations between potential risk factors and rCDI. At baseline, demographic and clinical characteristics were recorded; endogenous antibody levels were assessed using 2 enzyme-linked immunosorbent assays.

Results. 

A predictor of recurrence was age ≥65 years, and an antibody-mediated immune response to toxin B appears to be protective against rCDI.

Conclusions. 

Our findings demonstrate the importance of clinical as well as immunological risk factors in rCDI and provide more robust evidence for the protective effects of antibody to toxin B in the prevention of rCDI.

Clinical Trials Registration. NCT00350298.

Key words: epidemiology – risk factors – antibodies – toxin A – serology

10.1093/cid/ciw366 Received February 15, 2016.

Accepted May 7, 2016.

© The Author 2016. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail journals.permissions@oup.com.

Keywords: Research; Abstracts; Clostridium Difficile.

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Potential of #lactoferrin to prevent #antibiotic-induced #Clostridium difficile #infection (J Antimicrob Chemother., abstract)

[Source: Journal of Antimicrobial Chemotherapy, full page: (LINK). Abstract, edited.]

Potential of lactoferrin to prevent antibiotic-induced Clostridium difficile infection [      ]

C. H. Chilton 1, G. S. Crowther 1, K. Śpiewak 2, M. Brindell 2, G. Singh 3, M. H. Wilcox 1 and T. M. Monaghan 3,*

Author Affiliations: 1Leeds Institute for Molecular Medicine, University of Leeds, Leeds, UK 2Department of Inorganic Chemistry, Jagiellonian University, Krakow, Poland 3NIHR Biomedical Research Unit in Gastrointestinal and Liver Diseases at Nottingham University Hospitals NHS Trust and The University of Nottingham, Nottingham, UK

*Corresponding author. Tel: +44-(0)115-9249924; Fax: +44-(0)115-9709955; E-mail: tanya.monaghan@nottingham.ac.uk

Received August 8, 2015. Revision requested September 27, 2015. Revision received October 20, 2015. Accepted November 24, 2015.

 

Abstract

Objectives

Clostridium difficile infection (CDI) is a global healthcare problem. Recent evidence suggests that the availability of iron may be important for C. difficile growth. This study evaluated the comparative effects of iron-depleted (1% Fe3+ saturated) bovine apo-lactoferrin (apo-bLf) and iron-saturated (85% Fe3+ saturated) bovine holo-lactoferrin (holo-bLf) in a human in vitro gut model that simulates CDI.

Methods

Two parallel triple-stage chemostat gut models were inoculated with pooled human faeces and spiked with C. difficile spores (strain 027 210, PCR ribotype 027). Holo- or apo-bLf was instilled (5 mg/mL, once daily) for 35 days. After 7 days, clindamycin was instilled (33.9 mg/L, four times daily) to induce simulated CDI. Indigenous microflora populations, C. difficile total counts and spores, cytotoxin titres, short chain fatty acid concentrations, biometal concentrations, lactoferrin concentration and iron content of lactoferrin were monitored daily.

Results

In the apo-bLf model, germination of C. difficile spores occurred 6 days post instillation of clindamycin, followed by rapid vegetative cell proliferation and detectable toxin production. By contrast, in the holo-bLf model, only a modest vegetative cell population was observed until 16 days post antibiotic administration. Notably, no toxin was detected in this model. In separate batch culture experiments, holo-bLf prevented C. difficile vegetative cell growth and toxin production, whereas apo-bLf and iron alone did not.

Conclusions

Holo-bLf, but not apo-bLf, delayed C. difficile growth and prevented toxin production in a human gut model of CDI. This inhibitory effect may be iron independent. These observations suggest that bLf in its iron-saturated state could be used as a novel preventative or treatment strategy for CDI.

© The Author 2016. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy.

This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited.

Keywords: Research; Abstracts; Clostridium difficile; Lactoferrin.

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Better together: #bacteriophage combinations significantly reduce #Clostridium difficile #growth in vitro and proliferation in vivo (Antimicrob Agents Chemother., abstract)

[Source: Antimicrobial Agents and Chemotherapy, full page: (LINK). Abstract, edited.]

Better together: bacteriophage combinations significantly reduce Clostridium difficile growth in vitro and proliferation in vivo [      ]

Janet Y. Nale a, Janice Spencer b, Katherine R. Hargreaves a, Anthony M. Buckley b, Przemysław Trzepiński a,  Gillian R. Douce b# and Martha R. J. Clokie a#

Author Affiliations: aDepartment of Infection, Immunity and Inflammation, University of Leicester, Leicester, England, UK. bInstitute of Infection, Immunity and Inflammation, College of Medical, Veterinary and Life Sciences, Sir Graham Davies Building, University Place, University of Glasgow, Scotland, UK

 

ABSTRACT

Microbiome dysbiosis caused by antibiotic treatment has been associated with both the susceptibility and relapsing of Clostridium difficile infection (CDI). Bacteriophage (phage) therapy offers target specificity and dose amplification in situ, but few studies have focused on their use in CDI treatment. This mainly reflects the lack of strictly virulent phages that target this pathogen. Whilst it is widely accepted that temperate phages are unsuitable for therapeutic purposes due to their transduction potential, analysis of seven C. difficile phages confirmed that this impact could be curtailed by the application of multiple phage types. Here, host range analysis of six myoviruses and one siphovirus was conducted on 80 strains representing 21 major epidemic and clinically severe ribotypes. The phages had complementary coverage; lysing 18 and 62 of the ribotypes and strains tested respectively. Single-phage treatments of ribotypes 076, 014/020 and 027 strains showed an initial reduction in bacterial load followed by emergence of phage-resistant colonies. However, these colonies remained susceptible to phage infection with an unrelated phage. In contrast, specific phage combinations caused complete lysis of C. difficile in vitro and prevented the appearance of resistant/lysogenic clones. Using a hamster model, oral delivery of optimized phage combinations resulted in reduced C. difficile colonization 36 h post-infection. Interestingly, free phages were recovered from the bowel at this time. In a challenge model of the disease, phage treatment delayed the onset of symptoms by 33 h compared to untreated animals. These data demonstrate the therapeutic potential of phage combinations to treat CDI.

 

FOOTNOTES

#Address correspondence to: M. R. J. Clokie, mrjc1@le.ac.uk and G. R. Douce. Gillian.Douce@glasgow.ac.uk

Copyright © 2015 Nale et al.

This is an open-access article distributed under the terms of the Creative Commons Attribution 3.0 International license.

Keywords: Research; Abstracts; Antibiotics; Drugs Resistance; Clostridium Difficile; Bacteriophages.

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