scholarly journals Evaluation of antimicrobial activity of ceftaroline against Clostridium difficile and propensity to induce C. difficile infection in an in vitro human gut model

2013 ◽  
Vol 68 (8) ◽  
pp. 1842-1849 ◽  
Author(s):  
S. D. Baines ◽  
C. H. Chilton ◽  
G. S. Crowther ◽  
S. L. Todhunter ◽  
J. Freeman ◽  
...  
Keyword(s):  
Antimicrobial Activity ◽  
Clostridium Difficile ◽  
Human Gut

scholarly journals Evaluation of linezolid for the treatment of Clostridium difficile infection caused by epidemic strains using an in vitro human gut model

2011 ◽  
Vol 66 (7) ◽  
pp. 1537-1546 ◽  
Author(s):  
S. D. Baines ◽  
A. R. Noel ◽  
G. S. Huscroft ◽  
S. L. Todhunter ◽  
R. O'Connor ◽  
...  
Keyword(s):  
Clostridium Difficile ◽  
Clostridium Difficile Infection ◽  
Human Gut

scholarly journals Mecillinam: a low-risk antimicrobial agent for induction of Clostridium difficile infection in an in vitro human gut model

2009 ◽  
Vol 63 (4) ◽  
pp. 838-839 ◽  
Author(s):  
S. D. Baines ◽  
R. O'Connor ◽  
G. Huscroft ◽  
K. Saxton ◽  
J. Freeman ◽  
...  
Keyword(s):  
Clostridium Difficile ◽  
Antimicrobial Agent ◽  
Clostridium Difficile Infection ◽  
Low Risk ◽  
Human Gut

scholarly journals Evaluation of NVB302 versus vancomycin activity in an in vitro human gut model of Clostridium difficile infection

2012 ◽  
Vol 68 (1) ◽  
pp. 168-176 ◽  
Author(s):  
G. S. Crowther ◽  
S. D. Baines ◽  
S. L. Todhunter ◽  
J. Freeman ◽  
C. H. Chilton ◽  
...  
Keyword(s):  
Clostridium Difficile ◽  
Clostridium Difficile Infection ◽  
Human Gut

scholarly journals Probing Clostridium difficile infection in innovative human gut cellular models

2018 ◽  
Author(s):  
Blessing O. Anonye ◽  
Jack Hassall ◽  
Jamie Patient ◽  
Usanee Detamornrat ◽  
Afnan M. Aladdad ◽  
...  
Keyword(s):  
Clostridium Difficile ◽  
Epithelial Cells ◽  
Gradual Increase ◽  
Controlled Environment ◽  
Human Gut ◽  
Epithelial Monolayers ◽  
Cellular Models ◽  
Gut Colonization ◽  
D Model

AbstractInteractions of anaerobic gut bacteria, such as Clostridium difficile, with the intestinal mucosa have been poorly studied due to challenges in culturing anaerobes with the oxygen-requiring gut epithelium. Although gut colonization by C. difficile is a key determinant of disease outcome, precise mechanisms of mucosal attachment and spread remain unclear. Here, using human gut epithelial monolayers co-cultured within dual environment chambers, we demonstrate that C. difficile adhesion to gut epithelial cells is accompanied by a gradual increase in bacterial numbers. Prolonged infection causes redistribution of actin and loss of epithelial integrity, accompanied by production of C. difficile spores, toxins and bacterial filaments. This 2-D dual chamber system was used to examine C. difficile interactions with the commensal Bacteroides dorei, and interestingly, C. difficile growth is significantly reduced in presence of B. dorei. Furthermore, in novel multilayer and 3-D gut models containing a myofibroblast layer, C. difficile adheres more efficiently to epithelial cells, as compared to the 2-D model, leading to a quicker destruction of the epithelium. Our study describes new controlled environment human gut models that enable host-anaerobe and pathogen-commensal interaction studies in vitro.

scholarly journals Effects of Exposure of Clostridium difficile PCR Ribotypes 027 and 001 to Fluoroquinolones in a Human Gut Model

2008 ◽  
Vol 53 (2) ◽  
pp. 412-420 ◽  
Author(s):  
Katie Saxton ◽  
Simon D. Baines ◽  
Jane Freeman ◽  
Rachael O'Connor ◽  
Mark H. Wilcox
Keyword(s):  
Clostridium Difficile ◽  
Gut Microbiota ◽  
Spore Germination ◽  
Toxin Production ◽  
Human Gut ◽  
Ribotype 027 ◽  
Resistant Mutants ◽  
High Level ◽  
Pcr Ribotype 027

ABSTRACT The incidence of Clostridium difficile infection is increasing, with reports implicating fluoroquinolone use. A three-stage chemostat gut model was used to study the effects of three fluoroquinolones (ciprofloxacin, levofloxacin, and moxifloxacin) on the gut microbiota and two epidemic C. difficile strains, strains of PCR ribotypes 027 and 001, in separate experiments. C. difficile total viable counts, spore counts, and cytotoxin titers were determined. The emergence of C. difficile isolates with reduced antibiotic susceptibility was monitored with fluoroquinolone-containing medium, and molecular analysis of the quinolone resistance-determining region was performed. C. difficile spores were quiescent in the absence of fluoroquinolones. Instillation of each fluoroquinolone led to C. difficile spore germination and high-level cytotoxin production. High-level toxin production occurred after detectable spore germination in all experiments except those with C. difficile PCR ribotype 027 and moxifloxacin, in which marked cytotoxin production preceded detectable germination, which coincided with isolate recovery on fluoroquinolone-containing medium. Three C. difficile PCR ribotype 027 isolates and one C. difficile PCR ribotype 001 isolate from fluoroquinolone-containing medium exhibited elevated MICs (80 to ≥180 mg/liter) and possessed mutations in gyrA or gyrB. These in vitro results suggest that all fluoroquinolones have the propensity to induce C. difficile infection, regardless of their antianaerobe activities. Resistant mutants were seen only following moxifloxacin exposure.

scholarly journals Tolevamer Is Not Efficacious in the Neutralization of Cytotoxin in a Human Gut Model of Clostridium difficile Infection

2009 ◽  
Vol 53 (5) ◽  
pp. 2202-2204 ◽  
Author(s):  
Simon D. Baines ◽  
Jane Freeman ◽  
Mark H. Wilcox
Keyword(s):  
Clinical Trials ◽  
Clostridium Difficile ◽  
Phase Iii ◽  
Binding Agent ◽  
Human Gut ◽  
Toxin Binding ◽  
Phase Iii Clinical Trials ◽  
Recent Phase ◽  
Poor Efficacy

ABSTRACT The efficacy of tolevamer, a nonantimicrobial styrene derivative toxin-binding agent, in treating simulated Clostridium difficile infection in an in vitro human gut model was investigated. Tolevamer reduced neither the duration nor magnitude of cytotoxin activity by C. difficile, reflecting poor efficacy observed in recent phase III clinical trials.

scholarly journals Flexible cobamide metabolism in Clostridioides (Clostridium) difficile 630 Δerm

2019 ◽  
Author(s):  
Amanda N. Shelton ◽  
Xun Lyu ◽  
Michiko E. Taga
Keyword(s):  
Clostridium Difficile ◽  
De Novo ◽  
Genomic Analysis ◽  
Opportunistic Pathogen ◽  
Vitamin B ◽  
Uptake System ◽  
Human Gut ◽  
Clostridioides Difficile ◽  
Lower Ligand

AbstractClostridioides (Clostridium) difficile is an opportunistic pathogen known for its ability to colonize the human gut under conditions of dysbiosis. Several aspects of its carbon and amino acid metabolism have been investigated, but its cobamide (vitamin B12 and related cofactors) metabolism remains largely unexplored. C. difficile has seven predicted cobamide-dependent metabolisms encoded in its genome in addition to a nearly complete cobamide biosynthesis pathway and a cobamide uptake system. To address the importance of cobamides to C. difficile, we studied C. difficile 630 Δerm and mutant derivatives under cobamide-dependent conditions in vitro. Our results show that C. difficile can use a surprisingly diverse array of cobamides for methionine and deoxyribonucleotide synthesis, and can use alternative metabolites or enzymes, respectively, to bypass these cobamide-dependent processes. C. difficile 630 Δerm produces the cobamide pseudocobalamin when provided the early precursor 5-aminolevulinc acid or the late intermediate cobinamide, and produces other cobamides if provided an alternative lower ligand. The ability of C. difficile 630 Δerm to take up cobamides and Cbi at micromolar or lower concentrations requires the transporter BtuFCD. Genomic analysis revealed genetic variations in in the btuFCD locus of different C. difficile strains, which may result in differences in the ability to take up cobamides and Cbi. These results together demonstrate that, like other aspects of its physiology, cobamide metabolism in C. difficile is versatile.ImportanceThe ability of the opportunistic pathogen Clostridioides difficile to cause disease is closely linked to its propensity to adapt to conditions created by dysbiosis of the human gut microbiota. The cobamide (vitamin B12) metabolism of C. difficile has been underexplored, though it has seven metabolic pathways that are predicted to require cobamide-dependent enzymes. Here, we show that C. difficile cobamide metabolism is versatile, as it can use a surprisingly wide variety of cobamides and has alternative functions that can bypass some of its cobamide requirements. Furthermore, C. difficile does not synthesize cobamides de novo, but produces them when given cobamide precursors. Better understanding of C. difficile cobamide metabolism may lead to new strategies to treat and prevent C. difficile-associated disease.

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