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Novel approaches to treating Clostridium difficile-associated colitis.

ABSTRACT: Clostridium difficile is being recognized as a growing threat to many health-care systems. Epidemiology data shows that infection rates are soaring and the disease burden is increasing. Despite the efficacy of standard treatments, it is becoming evident that novel therapeutics will be required to tackle this disease. These new treatments aim to enhance the intestinal microbial barrier, activate the immune system and neutralize the toxins that mediate this disease. Many of these therapies are still in the beginning stages of investigation, however, in the next few years, more clinical data will become available to help implement many of these exciting new therapeutic approaches.

SUBMITTER: Padua D

PROVIDER: S-EPMC5979265 | biostudies-literature | 2016

REPOSITORIES: biostudies-literature

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Novel approaches to treating Clostridium difficile-associated colitis.

Padua David D Pothoulakis Charalabos C

Expert review of gastroenterology & hepatology 20151207 2

Clostridium difficile is being recognized as a growing threat to many health-care systems. Epidemiology data shows that infection rates are soaring and the disease burden is increasing. Despite the efficacy of standard treatments, it is becoming evident that novel therapeutics will be required to tackle this disease. These new treatments aim to enhance the intestinal microbial barrier, activate the immune system and neutralize the toxins that mediate this disease. Many of these therapies are sti ...[more]

PMID: 26643655

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Treating Clostridium difficile infection.

Project description: Not available

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Differentiating Clostridium difficile Colitis from Clostridium difficile Colonization in Ulcerative Colitis: A Role for Procalcitonin.

Project description:Background/aimsClostridium difficile infection (CDI) frequently complicates ulcerative colitis (UC) and can mimic disease flare. Differentiating UC flare from CDI remains a clinical challenge, particularly due to C. difficile colonization. Procalcitonin (PCT) is a serum biomarker for bacterial infections. We hypothesized that PCT would differentiate acute CDI from UC flare and C. difficile colonization.MethodsA single-center prospective cohort study was conducted from 2013 to 2016. All UC patients with a stool sample for C. difficile testing were eligible. A total of 117 patients were enrolled, while 20 were excluded. Chart review was performed.ResultsAmong 27 patients with CDI, median PCT was 60.7 (range 26-560.6) pg/mL, while among 90 patients without CDI, median PCT was 56.7 (range 25.1-2,252) pg/mL (p = 0.9). It was found that 14 patients with CDI responded completely to C. difficile treatment (CDI-R), while 8 patients did not and were diagnosed with UC flare (CDI-NR). For CDI-R, median PCT was 104.5 (range 26.3-560.6), compared to 40.3 (range 26.0-116.3) for CDI-NR (p = 0.036).ConclusionsIn UC patients presenting with diarrhea, serum PCT was not significantly higher in UC patients with positive C. difficile testing. However, PCT was significantly elevated in CDI-R versus CDI-NR, suggesting that PCT may have utility in making this discrimination.

| S-EPMC5899687 | biostudies-literature

Persistent and Recurrent Clostridium difficile Colitis.

Project description:Clostridium difficile infection (CDI) is the most frequent cause of nosocomial diarrhea. It has become a significant dilemma in the treatment of patients, and causes increasing morbidity that, in extreme cases, may result in death. Persistent and recurrent disease hamper attempts at eradication of this infection. Escalating levels of treatment and novel therapeutics are being utilized and developed to treat CDI. Further trials are warranted to definitively determine what protocols can be used to treat persistent and recurrent disease.

| S-EPMC4442717 | biostudies-other

Intravenous immunoglobulin therapy for severe Clostridium difficile colitis.

Project description:BACKGROUND: Many individuals have serum antibodies against Clostridium difficile toxins. Those with an impaired antitoxin response may be susceptible to recurrent, prolonged, or severe C difficile diarrhoea and colitis. AIMS: To examine whether treatment with intravenous immunoglobulin might be effective in patients with severe pseudomembranous colitis unresponsive to standard antimicrobial therapy. PATIENTS: Two patients with pseudomembranous colitis not responding to metronidazole and vancomycin were given normal pooled human immunoglobulin intravenously (200-300 mg/kg). METHODS: Antibodies against C difficile toxins were measured in nine immunoglobulin preparations by ELISA and by cytotoxin neutralisation assay. RESULTS: Both patients responded quickly as shown by resolution of diarrhoea, abdominal tenderness, and distension. All immunoglobulin preparations tested contained IgG against C difficile toxins A and B by ELISA and neutralised the cytotoxic activity of C difficile toxins in vitro at IgG concentrations of 0.4-1.6 mg/ml. CONCLUSION: Passive immunotherapy with intravenous immunoglobulin may be a useful addition to antibiotic therapy for severe, refractory C difficile colitis. IgG antitoxin is present in standard immunoglobulin preparations and C difficile toxin neutralising activity is evident at IgG concentrations which are readily achieved in the serum by intravenous immunoglobulin administration.

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Role of interleukin 23 signaling in Clostridium difficile colitis.

Project description:Clostridium difficile is currently the leading cause of hospital-acquired infections in the United States. Here, we observed increased interleukin 23 (IL-23) protein levels in human colon biopsy specimens positive for C. difficile toxins, compared with levels in negative controls (P = .008) We also investigated the role of IL-23 during C. difficile infection, using 2 distinct murine models. Mice lacking IL-23 signaling had a significant increase in survival (100% [12 mice]), compared with control mice (16.7%-50% [12 mice]). These data suggest a new potential drug target for human C. difficile treatment and indicate the first link between IL-23 and disease severity during murine infection.

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A small-molecule antivirulence agent for treating Clostridium difficile infection.

Project description:Clostridium difficile infection (CDI) is a worldwide health threat that is typically triggered by the use of broad-spectrum antibiotics, which disrupt the natural gut microbiota and allow this Gram-positive anaerobic pathogen to thrive. The increased incidence and severity of disease coupled with decreased response, high recurrence rates, and emergence of multiple antibiotic-resistant strains have created an urgent need for new therapies. We describe pharmacological targeting of the cysteine protease domain (CPD) within the C. difficile major virulence factor toxin B (TcdB). Through a targeted screen with an activity-based probe for this protease domain, we identified a number of potent CPD inhibitors, including one bioactive compound, ebselen, which is currently in human clinical trials for a clinically unrelated indication. This drug showed activity against both major virulence factors, TcdA and TcdB, in biochemical and cell-based studies. Treatment in a mouse model of CDI that closely resembles the human infection confirmed a therapeutic benefit in the form of reduced disease pathology in host tissues that correlated with inhibition of the release of the toxic glucosyltransferase domain (GTD). Our results show that this non-antibiotic drug can modulate the pathology of disease and therefore could potentially be developed as a therapeutic for the treatment of CDI.

| S-EPMC6025901 | biostudies-literature

Confocal laser endomicroscopy for in vivo diagnosis of Clostridium difficile associated colitis - a pilot study.

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| S-EPMC3602426 | biostudies-literature

Genetic risk factors for Clostridium difficile infection in ulcerative colitis.

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| S-EPMC3755009 | biostudies-literature

The antimicrobial peptide cathelicidin modulates Clostridium difficile-associated colitis and toxin A-mediated enteritis in mice.

Project description:BackgroundClostridium difficile mediates intestinal inflammation by releasing toxin A (TxA), a potent enterotoxin. Cathelicidins (Camp as gene name, LL-37 peptide in humans and mCRAMP peptide in mice) are antibacterial peptides that also posses anti-inflammatory properties.ObjectivesTo determine the role of cathelicidins in models of Clostridium difficile infection and TxA-mediated ileal inflammation and cultured human primary monocytes.DesignWild-type (WT) and mCRAMP-deficient (Camp(-/-)) mice were treated with an antibiotic mixture and infected orally with C difficile. Some mice were intracolonically given mCRAMP daily for 3 days. Ileal loops were also prepared in WT mice and treated with either saline or TxA and incubated for 4 h, while some TxA-treated loops were injected with mCRAMP.ResultsIntracolonic mCRAMP administration to C difficile-infected WT mice showed significantly reduced colonic histology damage, apoptosis, tissue myeloperoxidase (MPO) and tumour necrosis factor (TNF)α levels. Ileal mCRAMP treatment also significantly reduced histology damage, tissue apoptosis, MPO and TNFα levels in TxA-exposed ileal loops. WT and Camp(-/-) mice exhibited similar intestinal responses in both models, implying that C difficile/TxA-induced endogenous cathelicidin may be insufficient to modulate C difficile/TxA-mediated intestinal inflammation. Both LL-37 and mCRAMP also significantly reduced TxA-induced TNFα secretion via inhibition of NF-κB phosphorylation. Endogenous cathelicidin failed to control C difficile and/or toxin A-mediated inflammation and even intestinal cathelicidin expression was increased in humans and mice.ConclusionExogenous cathelicidin modulates C difficile colitis by inhibiting TxA-associated intestinal inflammation. Cathelicidin administration may be a new anti-inflammatory treatment for C difficile toxin-associated disease.

| S-EPMC3737259 | biostudies-literature

Systemic Inflammatory Responses in Ulcerative Colitis Patients and Clostridium difficile Infection.

Project description:Background/aimsFinding differences in systemic inflammatory response in ulcerative colitis (UC), UC with Clostridium difficile infection (CDI), and CDI could lead to a better ability to differentiate between UC with symptomatic CDI and UC with C. difficile colonization, and could identify specific inflammatory pathways for UC or CDI, which could be therapeutic targets.MethodsWe prospectively collected sera from symptomatic UC patients whose stools were tested for toxigenic C. difficile, and from CDI patients who did not have UC (CDI-noUC). The UC patients with positive tests (UC-CDI) were further categorized into responders to CDI treatment (UC-CDI-R) and non-responders (UC-CDI-NR). We compared serum inflammatory mediators among groups using unadjusted and adjusted multivariable statistics.ResultsWe included 117 UC [27 UC-CDI, 90 UC without CDI (UC-noCDI)] and 16 CDI-noUC patients. Principal component analysis (PCA) did not reveal significant differences either between UC-CDI and UC-noCDI groups, or between UC-CDI-R and UC-CDI-NR groups. In contrast, the PCA showed significant separation between the UC and CDI-noUC groups (P = 0.002). In these two groups, hepatocyte growth factor (HGF) and chemokine (C-C motif) ligand 2 (CCL2) levels were significantly lower and IL-23 levels were higher in UC patients in multivariable analyses. The model to distinguish UC from CDI including IL-23, HGF, CCL2, age, gender, and HGB had an AuROC of 0.93.ConclusionInflammatory profiles could not distinguish UC-CDI from UC-noCDI, and UC-CDI-R from UC-CDI-NR. However, the UC and CDI-noUC groups were significantly different. Future work should examine whether therapeutic agents inhibiting IL-23 or stimulating HGF can treat UC.

| S-EPMC6015554 | biostudies-literature

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