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Lin Q, Li Z, Lu L, Xu H, Lou E, Chen A, Sun D, Zhang W, Zhu W, Yee EU, Sears PS, Chen X, Kelly CP. Budesonide, an anti-inflammatory drug, exacerbate clostridioides difficile colitis in mice. Biomed Pharmacother 2023; 167:115489. [PMID: 37713991 DOI: 10.1016/j.biopha.2023.115489] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2023] [Revised: 09/08/2023] [Accepted: 09/11/2023] [Indexed: 09/17/2023] Open
Abstract
BACKGROUND AND AIMS Clostridioides difficile infection (CDI) induces intense acute inflammatory responses through toxin release. A combination of antibiotic and anti-inflammatory agents is sometimes recommended in severe, non-responsive cases, although clinical trials have been inconclusive, raising concerns about potential complications. This study aims to investigate the effect of budesonide and mesalamine in the treatment of CDI in a murine model, by evaluating the combination of fidaxomicin and these anti-inflammatory drugs. METHOD C57BL/6 J female mice pretreated with an antimicrobial mixture were challenged with C. difficile VPI 10463 or culture media by gavage. After the challenge, mice received placebo, fidaxomicin alone (20 mg/kg), or fidaxomicin combined with mesalamine (200, 400 mg/kg) or budesonide (0.2, 1, 10 mg/kg) for 5 days. The mice were monitored for 7 days with weight and survival. Colon and cecum tissues were harvested for histological assessment. RESULTS CDI of mice caused 80% mortality. Fidaxomicin completely protected against CDI in all parameters (weight, survival and pathscores). Mortality rates were up to 90%, 70% in budesonide(10 mg/kg) and mesalamine (400 mg/kg) treatment group, respectively. Budesonide (0.02,0.1 and 1 mg/kg) adjunction to fidaxomicin worsened the disease outcome according to all tested parameters. While mesalamine in combination with fidaxomicin (200, 400 mg/kg) did not lead to any deaths during CDI treatment, it did not provide additional benefits. CONCLUSIONS Anti-inflammatory drugs including corticosteroid therapy may worsen the incidence and severity of CDI in this mouse model. These studies may have important clinical implications for understanding the role of anti-inflammatory/ corticosteroid therapy in CDI and inflammatory bowel disease management.
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Affiliation(s)
- Qianyun Lin
- Department of Gastroenterology, Beijing Friendship Hospital, Beijing Key Laboratory for Precancerous Lesion of Digestive Disease, National Clinical Research Center for Digestive Disease, Beijing Digestive Disease Center, Capital Medical University, Beijing, China; Divisions of Gastroenterology, Beth Israel Deaconess Medical Centre, Boston, MA, USA
| | - Zitong Li
- Guangdong Provincial Key Laboratory of Gastroenterology, Department of Gastroenterology, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Lei Lu
- Section of Neonatology, Department of Paediatrics and Medicine, the University of Chicago, Chicago, IL, USA
| | - Hua Xu
- Divisions of Gastroenterology, Beth Israel Deaconess Medical Centre, Boston, MA, USA
| | - Eddie Lou
- Divisions of Gastroenterology, Beth Israel Deaconess Medical Centre, Boston, MA, USA
| | - Alyssa Chen
- Divisions of Gastroenterology, Beth Israel Deaconess Medical Centre, Boston, MA, USA
| | - Dustin Sun
- Divisions of Gastroenterology, Beth Israel Deaconess Medical Centre, Boston, MA, USA
| | - Wuyi Zhang
- Divisions of Gastroenterology, Beth Israel Deaconess Medical Centre, Boston, MA, USA
| | - Weishu Zhu
- Divisions of Gastroenterology, Beth Israel Deaconess Medical Centre, Boston, MA, USA
| | - Eric U Yee
- Department of Pathology, Beth Israel Deaconess Medical Centre, Boston, MA, USA; Department of Pathology, University of Arkansas for Medical Sciences, Little Rock, AR, USA
| | | | - Xinhua Chen
- Divisions of Gastroenterology, Beth Israel Deaconess Medical Centre, Boston, MA, USA.
| | - Ciaran P Kelly
- Divisions of Gastroenterology, Beth Israel Deaconess Medical Centre, Boston, MA, USA.
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Son YJ, Kim YR, Oh SH, Jung S, Ciufolini MA, Hwang HJ, Kwak JH, Pai H. Micrococcin P2 Targets Clostridioides difficile. JOURNAL OF NATURAL PRODUCTS 2022; 85:1928-1935. [PMID: 35816693 DOI: 10.1021/acs.jnatprod.2c00120] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/15/2023]
Abstract
Clostridioides difficile infection is a global public health threat. Extensive in vitro assays using clinical isolates have identified micrococcin P2 (MP2, 1) as a particularly effective anti-C. difficile agent. MP2 possesses a mode of action that differs from other antibiotics and pharmacokinetic properties that render it especially promising. Its time-kill studies have been investigated using hypervirulent C. difficile ribotype 027. DSS (dextran sulfate sodium)-induced in vivo mouse studies with that strain indicate that 1 is better than vancomycin and fidaxomicin. Thus, micrococcin P2 is a valuable platform to be exploited for the development of new anti-C. difficile antibiotics.
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Affiliation(s)
- Young-Jin Son
- A&J Science Co., Ltd., 80 Chumbok Road, Dong Gu, Daegu, 41061, Republic of Korea
- Department of Agricultural Biotechnology, Seoul National University, 1 Gwanak Road, Gwanak-gu, Seoul, 08826, Republic of Korea
| | - Young-Rok Kim
- School of Life Science, Handong Global University, 558 Handong Road, Heunghae-eup, Buk-gu, Pohang, 37554, Republic of Korea
| | - Sang-Hun Oh
- School of Life Science, Handong Global University, 558 Handong Road, Heunghae-eup, Buk-gu, Pohang, 37554, Republic of Korea
| | - Sungji Jung
- School of Life Science, Handong Global University, 558 Handong Road, Heunghae-eup, Buk-gu, Pohang, 37554, Republic of Korea
| | - Marco A Ciufolini
- Department of Chemistry, University of British Columbia, 2036 Main Mall, Vancouver, BC V6K 1Z1, Canada
| | - Hee-Jong Hwang
- A&J Science Co., Ltd., 80 Chumbok Road, Dong Gu, Daegu, 41061, Republic of Korea
| | - Jin-Hwan Kwak
- School of Life Science, Handong Global University, 558 Handong Road, Heunghae-eup, Buk-gu, Pohang, 37554, Republic of Korea
| | - Hyunjoo Pai
- Department of Internal Medicine, College of Medicine, Hanyang University, 222 Wangsimni Road, Seongdong-gu, Seoul, 04763, Republic of Korea
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Santos AAQA, Costa DVS, Foschetti DA, Duarte ASG, Martins CS, Soares PMG, Castelucci P, Brito GAC. P2X7 receptor blockade decreases inflammation, apoptosis, and enteric neuron loss during Clostridioides difficile toxin A-induced ileitis in mice. World J Gastroenterol 2022; 28:4075-4088. [PMID: 36157120 PMCID: PMC9403433 DOI: 10.3748/wjg.v28.i30.4075] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/09/2021] [Revised: 05/04/2022] [Accepted: 07/11/2022] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Clostridioides difficile (C. difficile) is the most common pathogen causing health care-associated infections. C. difficile TcdA and TcdB have been shown to activate enteric neurons; however, what population of these cells is more profoundly influenced and the mechanism underlying these effects remain unknown.
AIM To characterize a specific population of TcdA-affected myenteric neurons and investigate the role of the P2X7 receptor in TcdA-induced ileal inflammation, cell death, and the changes in the enteric nervous system in mice.
METHODS Swiss mice were used to model TcdA-induced ileitis in ileal loops exposed to TcdA (50 μg/Loop) for 4 h. To investigate the role of the P2X7 receptor, Brilliant Blue G (50 mg/kg, i.p.), which is a nonspecific P2X7 receptor antagonist, or A438079 (0.7 μg/mouse, i.p.), which is a competitive P2X7 receptor antagonist, were injected one hour prior to TcdA challenge. Ileal samples were collected to analyze the expression of the P2X7 receptor (by quantitative real-time polymerase chain reaction and immunohistochemistry), the population of myenteric enteric neurons (immunofluorescence), histological damage, intestinal inflammation, cell death (terminal deoxynucleotidyltransferase-mediated dUTP-biotin nick end labeling), neuronal loss, and S100B synthesis (immunohistochemistry).
RESULTS TcdA upregulated (P < 0.05) the expression of the P2X7 receptor gene in the ileal tissues, increasing the level of this receptor in myenteric neurons compared to that in control mice. Comparison with the control mice indicated that TcdA promoted (P < 0.05) the loss of myenteric calretinin+ (Calr) and choline acetyltransferase+ neurons and increased the number of nitrergic+ and Calr+ neurons expressing the P2X7 receptor. Blockade of the P2X7 receptor decreased TcdA-induced intestinal damage, cytokine release [interleukin (IL)-1β, IL-6, IL-8, and tumor necrosis factor-α], cell death, enteric neuron loss, and S100B synthesis in the mouse ileum.
CONCLUSION Our findings demonstrated that TcdA induced the upregulation of the P2X7 receptor, which promoted enteric neuron loss, S100B synthesis, tissue damage, inflammation, and cell death in the mouse ileum. These findings contribute to the future directions in understanding the mechanism involved in intestinal dysfunction reported in patients after C. difficile infection.
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Affiliation(s)
- Ana A Q A Santos
- Department of Morphology, School of Medicine, Federal University of Ceara, Fortaleza 60430-170, Ceara, Brazil
| | - Deiziane V S Costa
- Department of Morphology, School of Medicine, Federal University of Ceara, Fortaleza 60430-170, Ceara, Brazil
- Department of Physiology and Pharmacology, School of Medicine, Federal University of Ceará, Fortaleza 60430-170, Ceara, Brazil
| | - Danielle A Foschetti
- Department of Pathology and Legal Medicine, School of Medicine, Federal University of Ceara, Fortaleza 60430-170, Ceara, Brazil
| | - Antoniella S G Duarte
- Department of Morphology (UFC), Federal University of Ceara, Fortaleza 60430-170, Ceara, Brazil
| | - Conceição S Martins
- Department of Morphology, School of Medicine, Federal University of Ceara, Fortaleza 60430-170, Ceara, Brazil
| | - Pedro M G Soares
- Department of Morphology, School of Medicine, Federal University of Ceara, Fortaleza 60430-170, Ceara, Brazil
| | - Patricia Castelucci
- Department of Anatomy, Institute of Biomedical Sciences, University of São Paulo, Sao Paulo 05508-270, Brazil
| | - Gerly A C Brito
- Department of Morphology, Federal University of Ceara, Fortaleza 60140-170, Ceara, Brazil
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Castro-Córdova P, Mendoza-León MJ, Paredes-Sabja D. Using a ligate intestinal loop mouse model to investigate Clostridioides difficile adherence to the intestinal mucosa in aged mice. PLoS One 2021; 16:e0261081. [PMID: 34936648 PMCID: PMC8694449 DOI: 10.1371/journal.pone.0261081] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2021] [Accepted: 11/23/2021] [Indexed: 11/21/2022] Open
Abstract
Interaction of Clostridioides difficile spores with the intestinal mucosa contributes to the persistence and recurrence of the infection. Advanced age is one of the main risk factors for C. difficile infection and recurrence of the disease. However, interaction of C. difficile spores with the intestinal mucosa during aging has not been evaluated. In the present work, using intestinal ligated loop technique in a mouse model, we analyzed C. difficile spore adherence and internalization to the ileum and colonic mucosa during aging. Additionally, we provide visual documentation of the critical steps of the procedure. Consequently, our data suggest that spore internalization in the ileum and colonic mucosa is higher in elderly mice rather than adults or young mice. Also, our data suggest that spore adherence to the ileum and colonic mucosa decreases with aging.
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Affiliation(s)
- Pablo Castro-Córdova
- Facultad de Ciencias de la Vida, Microbiota-Host Interactions and Clostridia Research Group, Departamento de Ciencias Biológicas, Universidad Andrés Bello, Santiago, Chile
- ANID-Millennium Science Initiative Program—Millennium Nucleus in the Biology of the Intestinal Microbiota, Santiago, Chile
| | - María José Mendoza-León
- Facultad de Ciencias de la Vida, Microbiota-Host Interactions and Clostridia Research Group, Departamento de Ciencias Biológicas, Universidad Andrés Bello, Santiago, Chile
- ANID-Millennium Science Initiative Program—Millennium Nucleus in the Biology of the Intestinal Microbiota, Santiago, Chile
| | - Daniel Paredes-Sabja
- ANID-Millennium Science Initiative Program—Millennium Nucleus in the Biology of the Intestinal Microbiota, Santiago, Chile
- Department of Biology, Texas A&M University, College Station, Texas, United States of America
- * E-mail:
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Wang J, Ortiz C, Fontenot L, Mukhopadhyay R, Xie Y, Chen X, Feng H, Pothoulakis C, Koon HW. Therapeutic Mechanism of Macrophage Inflammatory Protein 1 α Neutralizing Antibody (CCL3) in Clostridium difficile Infection in Mice. J Infect Dis 2021; 221:1623-1635. [PMID: 31793629 DOI: 10.1093/infdis/jiz640] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2019] [Accepted: 12/02/2019] [Indexed: 12/17/2022] Open
Abstract
BACKGROUND Clostridium difficile infection (CDI) causes diarrhea and colitis. We aimed to find a common pathogenic pathway in CDI among humans and mice by comparing toxin-mediated effects in human and mouse colonic tissues. METHOD Using multiplex enzyme-linked immunosorbent assay, we determined the cytokine secretion of toxin A- and B-treated human and mouse colonic explants. RESULTS Toxin A and toxin B exposure to fresh human and mouse colonic explants caused different patterns of cytokine secretion. Toxin A induced macrophage inflammatory protein (MIP) 1α secretion in both human and mouse explants. Toxin A reduced the expression of chloride anion exchanger SLC26A3 expression in mouse colonic explants and human colonic epithelial cells. Patients with CDI had increased colonic MIP-1 α expression and reduced colonic SLC26A3 (solute carrier family 26, member 3) compared with controls. Anti-MIP-1 α neutralizing antibody prevented death, ameliorated colonic injury, reduced colonic interleukin 1β (IL-1β) messenger RNA expression, and restored colonic SLC26a3 expression in C. difficile-infected mice. The anti-MIP-1 α neutralizing antibody prevented CDI recurrence. SLC26a3 inhibition augmented colonic IL-1 β messenger RNA expression and abolished the protective effect of anti-MIP-1 α neutralizing antibody in mice with CDI. CONCLUSION MIP-1 α is a common toxin A-dependent chemokine in human and mouse colon. MIP-1 α mediates detrimental effects by reducing SLC26a3 and enhancing IL-1 β expression in the colon.
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Affiliation(s)
- Jiani Wang
- Vatche and Tamar Manoukian Division of Digestive Diseases, David Geffen School of Medicine at the University of California Los Angeles, Los Angeles, California, USA.,Department of Gastroenterology, First Affiliated Hospital, China Medical University, Shenyang City, Liaoning Province, China
| | - Christina Ortiz
- Vatche and Tamar Manoukian Division of Digestive Diseases, David Geffen School of Medicine at the University of California Los Angeles, Los Angeles, California, USA
| | - Lindsey Fontenot
- Vatche and Tamar Manoukian Division of Digestive Diseases, David Geffen School of Medicine at the University of California Los Angeles, Los Angeles, California, USA
| | - Riya Mukhopadhyay
- Vatche and Tamar Manoukian Division of Digestive Diseases, David Geffen School of Medicine at the University of California Los Angeles, Los Angeles, California, USA
| | - Ying Xie
- Vatche and Tamar Manoukian Division of Digestive Diseases, David Geffen School of Medicine at the University of California Los Angeles, Los Angeles, California, USA.,Department of Gastroenterology, First Affiliated Hospital, China Medical University, Shenyang City, Liaoning Province, China
| | - Xinhua Chen
- Division of Gastroenterology, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA
| | - Hanping Feng
- Department of Microbial Pathogenesis, School of Dentistry, University of Maryland, Maryland, Baltimore, USA
| | - Charalabos Pothoulakis
- Vatche and Tamar Manoukian Division of Digestive Diseases, David Geffen School of Medicine at the University of California Los Angeles, Los Angeles, California, USA
| | - Hon Wai Koon
- Vatche and Tamar Manoukian Division of Digestive Diseases, David Geffen School of Medicine at the University of California Los Angeles, Los Angeles, California, USA
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Kaden-Volynets V, Günther C, Zimmermann J, Beisner J, Becker C, Bischoff SC. Deletion of the Casp8 gene in mice results in ileocolitis, gut barrier dysfunction, and malassimilation, which can be partially attenuated by inulin or sodium butyrate. Am J Physiol Gastrointest Liver Physiol 2019; 317:G493-G507. [PMID: 31411503 DOI: 10.1152/ajpgi.00297.2018] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Genetically modified mice have been successfully used as models for inflammatory bowel diseases; however, dietary effects were poorly examined. Here, we studied the impact of particular nutrients and supplements on gut functions related to the knockout of the epithelial caspase-8 gene. Caspase-8 knockout (Casp8∆IEC) and control (Casp8fl) mice were fed for 4 wk a control diet (CD) enriched with 10% inulin (CD-Inu) or 5% sodium butyrate (CD-But) while having free access to plain water or water supplemented with 30% fructose (+F). Body weight changes, intestinal inflammation, and selected markers for barrier function and of liver steatosis were assessed. Casp8∆IEC mice developed ileocolitis accompanied by changes in intestinal barrier morphology and reduced expression of barrier-related genes such as mucin-2 (Muc2) and defensins in the ileum and Muc2 in the colon. Casp8∆IEC mice fed a CD also showed impaired body weight gain compared with Casp8fl mice, which was even more pronounced in mice receiving water supplemented with fructose. Furthermore, we observed a marked liver steatosis and inflammation in some but not all Casp8∆IEC mice under a CD, which was on average similar to that observed in control mice under a fructose-rich diet. Hepatic lipid accumulation, as well as markers of ileal barrier function, but not intestinal pathohistology or body weight loss, were attenuated by diets enriched with inulin or butyrate, especially in the absence of fructose supplementation. Our data show that ileocolitis, barrier dysfunction, and malassimilation in Caspase-8 knockout mice can be partially attenuated by oral inulin or butyrate supplementation.NEW & NOTEWORTHY Genetic mouse models for ileocolitis are important to understand inflammatory bowel disease in humans. We examined dietetic factors that might aggravate or attenuate ileocolitis and related pathologies in such a model. Deletion of the caspase-8 gene results not only in ileocolitis but also in gut barrier dysfunction, liver steatosis, and malassimilation, which can be partially attenuated by oral inulin or sodium butyrate. Our data indicate that diet modifications can contribute to disease variability and therapy.
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Affiliation(s)
| | - Claudia Günther
- Medical Clinic 1, Department of Medicine, University Hospital Erlangen, Friedrich-Alexander-University, Erlangen, Germany
| | - Julia Zimmermann
- Department of Nutritional Medicine, University of Hohenheim. Stuttgart, Germany
| | - Julia Beisner
- Department of Nutritional Medicine, University of Hohenheim. Stuttgart, Germany
| | - Christoph Becker
- Medical Clinic 1, Department of Medicine, University Hospital Erlangen, Friedrich-Alexander-University, Erlangen, Germany
| | - Stephan C Bischoff
- Department of Nutritional Medicine, University of Hohenheim. Stuttgart, Germany
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Shelby RD, Tengberg N, Conces M, Olson JK, Navarro JB, Bailey MT, Goodman SD, Besner GE. Development of a Standardized Scoring System to Assess a Murine Model of Clostridium difficile Colitis. J INVEST SURG 2019; 33:887-895. [PMID: 30892111 DOI: 10.1080/08941939.2019.1571129] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/05/2023]
Abstract
Background: Clostridium difficile infection is the most common cause of antimicrobial-associated diarrhea. Our aim was to introduce a novel and efficient clinical sickness score (CSS), and to define a detailed histologic injury score (HIS) in a murine model of C. difficile colitis. Methods: Mice received an antibiotic cocktail (kanamycin, gentamicin, colistin, metronidazole, and vancomycin) for 96 h. After 48 h, mice received an intraperitoneal injection of clindamycin, followed by oral C. difficile (1.5 × 107 CFU). Signs of sickness were scored using a novel CSS (range 0-12) with scores ≥6 consistent with C. difficile colitis. Intestinal tissue was analyzed utilizing an adapted HIS (range 0-9) with scores ≥4 consistent with C. difficile colitis. Stool was analyzed for C. difficile, and survival evaluated. Results: No control mice showed signs of sickness, whereas 23% of mice receiving antibiotics alone and 65% of mice exposed to antibiotics and subsequently C. difficile demonstrated signs of sickness (p = 0.0134). No control mice had histologic injury, whereas 8% of mice receiving antibiotics alone and 75% of mice exposed to antibiotics followed by C. difficile had evidence of histologic injury (p = 0.0001). Mice exposed to C. difficile lost more weight, although not significant (p = 0.070). Mice that received C. difficile had decreased survival compared to control mice and mice receiving antibiotics only (p = 0.03). Conclusions: We have developed a novel clinical scoring system, and detailed histological grading system, that enables the objective evaluation of a murine C. difficile colitis model. This model allows the study of this disease in a host that demonstrates clinical and histologic signs comparable to human C. difficile infection. This will allow for improved study of therapeutics for this disease in the future.
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Affiliation(s)
- Rita D Shelby
- Center for Perinatal Research, The Research Institute at Nationwide Children's Hospital, Department of Pediatric Surgery, Nationwide Children's Hospital, Columbus, OH, USA
| | - Natalie Tengberg
- Center for Perinatal Research, The Research Institute at Nationwide Children's Hospital, Department of Pediatric Surgery, Nationwide Children's Hospital, Columbus, OH, USA
| | - Miriam Conces
- Department of Pathology, Nationwide Children's Hospital, Columbus, OH, USA
| | - Jacob K Olson
- Center for Perinatal Research, The Research Institute at Nationwide Children's Hospital, Department of Pediatric Surgery, Nationwide Children's Hospital, Columbus, OH, USA
| | - Jason B Navarro
- Center for Microbial Pathogenesis, The Research Institute at Nationwide Children's Hospital, Columbus, OH, USA
| | - Michael T Bailey
- Center for Microbial Pathogenesis, The Research Institute at Nationwide Children's Hospital, Columbus, OH, USA
| | - Steven D Goodman
- Center for Microbial Pathogenesis, The Research Institute at Nationwide Children's Hospital, Columbus, OH, USA
| | - Gail E Besner
- Center for Perinatal Research, The Research Institute at Nationwide Children's Hospital, Department of Pediatric Surgery, Nationwide Children's Hospital, Columbus, OH, USA
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Wang J, Ghali S, Xu C, Mussatto CC, Ortiz C, Lee EC, Tran DH, Jacobs JP, Lagishetty V, Faull KF, Moller T, Rossetti M, Chen X, Koon HW. Ceragenin CSA13 Reduces Clostridium difficile Infection in Mice by Modulating the Intestinal Microbiome and Metabolites. Gastroenterology 2018; 154:1737-1750. [PMID: 29360463 PMCID: PMC5927842 DOI: 10.1053/j.gastro.2018.01.026] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/28/2017] [Revised: 12/21/2017] [Accepted: 01/15/2018] [Indexed: 01/01/2023]
Abstract
BACKGROUND & AIMS Clostridium difficile induces intestinal inflammation by releasing toxins A and B. The antimicrobial compound cationic steroid antimicrobial 13 (CSA13) has been developed for treating gastrointestinal infections. The CSA13-Eudragit formulation can be given orally and releases CSA13 in the terminal ileum and colon. We investigated whether this form of CSA13 reduces C difficile infection (CDI) in mice. METHODS C57BL/6J mice were infected with C difficile on day 0, followed by subcutaneous administration of pure CSA13 or oral administration of CSA13-Eudragit (10 mg/kg/d for 10 days). Some mice were given intraperitoneal vancomycin (50 mg/kg daily) on days 0-4 and relapse was measured after antibiotic withdrawal. The mice were monitored until day 20; colon and fecal samples were collected on day 3 for analysis. Blood samples were collected for flow cytometry analyses. Fecal pellets were collected each day from mice injected with CSA13 and analyzed by high-performance liquid chromatography or 16S sequencing; feces were also homogenized in phosphate-buffered saline and fed to mice with CDI via gavage. RESULTS CDI of mice caused 60% mortality, significant bodyweight loss, and colonic damage 3 days after infection; these events were prevented by subcutaneous injection of CSA13 or oral administration CSA13-Eudragit. There was reduced relapse of CDI after administration of CSA13 was stopped. Levels of CSA13 in feces from mice given CSA13-Eudragit were significantly higher than those of mice given subcutaneous CSA13. Subcutaneous and oral CSA13 each significantly increased the abundance of Peptostreptococcaceae bacteria and reduced the abundance of C difficile in fecal samples of mice. When feces from mice with CDI and given CSA13 were fed to mice with CDI that had not received CSA13, the recipient mice had significantly increased rates of survival. CSA13 reduced fecal levels of inflammatory metabolites (endocannabinoids) and increased fecal levels of 4 protective metabolites (ie, citrulline, 3-aminoisobutyric acid, retinol, and ursodeoxycholic acid) in mice with CDI. Oral administration of these CSA13-dependent protective metabolites reduced the severity of CDI. CONCLUSIONS In studies of mice, we found the CSA13-Eudragit formulation to be effective in eradicating CDI by modulating the intestinal microbiota and metabolites.
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Affiliation(s)
- Jiani Wang
- Center for Inflammatory Bowel Diseases, Vatche and Tamar Manoukian Division of Digestive Diseases, David Geffen School of Medicine at the University of California Los Angeles, Los Angeles, CA 90095,Department of Gastroenterology, First Affiliated Hospital, China Medical University, Shenyang City, Liaoning Province, China
| | - Sally Ghali
- Center for Inflammatory Bowel Diseases, Vatche and Tamar Manoukian Division of Digestive Diseases, David Geffen School of Medicine at the University of California Los Angeles, Los Angeles, CA 90095
| | - Chunlan Xu
- Center for Inflammatory Bowel Diseases, Vatche and Tamar Manoukian Division of Digestive Diseases, David Geffen School of Medicine at the University of California Los Angeles, Los Angeles, CA 90095,The Key Laboratory for Space Bioscience and Biotechnology, School of Life Science, Northwestern Polytechnical University, Xian, Shaanxi Province, China
| | - Caroline C. Mussatto
- Center for Inflammatory Bowel Diseases, Vatche and Tamar Manoukian Division of Digestive Diseases, David Geffen School of Medicine at the University of California Los Angeles, Los Angeles, CA 90095
| | - Christina Ortiz
- Center for Inflammatory Bowel Diseases, Vatche and Tamar Manoukian Division of Digestive Diseases, David Geffen School of Medicine at the University of California Los Angeles, Los Angeles, CA 90095
| | - Elaine C. Lee
- Center for Inflammatory Bowel Diseases, Vatche and Tamar Manoukian Division of Digestive Diseases, David Geffen School of Medicine at the University of California Los Angeles, Los Angeles, CA 90095
| | - Diana H. Tran
- Center for Inflammatory Bowel Diseases, Vatche and Tamar Manoukian Division of Digestive Diseases, David Geffen School of Medicine at the University of California Los Angeles, Los Angeles, CA 90095
| | - Jonathan P. Jacobs
- Center for Inflammatory Bowel Diseases, Vatche and Tamar Manoukian Division of Digestive Diseases, David Geffen School of Medicine at the University of California Los Angeles, Los Angeles, CA 90095
| | - Venu Lagishetty
- Center for Inflammatory Bowel Diseases, Vatche and Tamar Manoukian Division of Digestive Diseases, David Geffen School of Medicine at the University of California Los Angeles, Los Angeles, CA 90095
| | - Kym F. Faull
- Pasarow Mass Spectrometry Laboratory, Department of Psychiatry and Biobehavioral Sciences, David Geffen School of Medicine at the University of California Los Angeles, Los Angeles, CA 90095
| | - Travis Moller
- Pasarow Mass Spectrometry Laboratory, Department of Psychiatry and Biobehavioral Sciences, David Geffen School of Medicine at the University of California Los Angeles, Los Angeles, CA 90095
| | - Maura Rossetti
- Immunogenetics Center, Department of Pathology, David Geffen School of Medicine at the University of California Los Angeles, Los Angeles, CA 90095
| | - Xinhua Chen
- Division of Gastroenterology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215
| | - Hon Wai Koon
- Center for Inflammatory Bowel Diseases, Vatche and Tamar Manoukian Division of Digestive Diseases, David Geffen School of Medicine at the University of California Los Angeles, Los Angeles, California.
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Koon HW, Wang J, Mussatto CC, Ortiz C, Lee EC, Tran DHN, Chen X, Kelly CP, Pothoulakis C. Fidaxomicin and OP-1118 Inhibit Clostridium difficile Toxin A- and B-Mediated Inflammatory Responses via Inhibition of NF-κB Activity. Antimicrob Agents Chemother 2018; 62:e01513-17. [PMID: 29038278 PMCID: PMC5740352 DOI: 10.1128/aac.01513-17] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2017] [Accepted: 10/12/2017] [Indexed: 01/05/2023] Open
Abstract
Clostridium difficile causes diarrhea and colitis by releasing toxin A and toxin B. In the human colon, both toxins cause intestinal inflammation and stimulate tumor necrosis factor alpha (TNF-α) expression via the activation of NF-κB. It is well established that the macrolide antibiotic fidaxomicin is associated with reduced relapses of C. difficile infection. We showed that fidaxomicin and its primary metabolite OP-1118 significantly inhibited toxin A-mediated intestinal inflammation in mice in vivo and toxin A-induced cell rounding in vitro We aim to determine whether fidaxomicin and OP-1118 possess anti-inflammatory effects against toxin A and toxin B in the human colon and examine the mechanism of this response. We used fresh human colonic explants, NCM460 human colonic epithelial cells, and RAW264.7 mouse macrophages to study the mechanism of the activity of fidaxomicin and OP-1118 against toxin A- and B-mediated cytokine expression and apoptosis. Fidaxomicin and OP-1118 dose-dependently inhibited toxin A- and B-induced TNF-α and interleukin-1β (IL-1β) mRNA expression and histological damage in human colonic explants. Fidaxomicin and OP-1118 inhibited toxin A-mediated NF-κB phosphorylation in human and mouse intestinal mucosae. Fidaxomicin and OP-1118 also inhibited toxin A-mediated NF-κB phosphorylation and TNF-α expression in macrophages, which was reversed by the NF-κB activator phorbol myristate acetate (PMA). Fidaxomicin and OP-1118 prevented toxin A- and B-mediated apoptosis in NCM460 cells, which was reversed by the addition of PMA. PMA reversed the cytoprotective effect of fidaxomicin and OP-1118 in toxin-exposed human colonic explants. Fidaxomicin and OP-1118 inhibit C. difficile toxin A- and B-mediated inflammatory responses, NF-κB phosphorylation, and tissue damage in the human colon.
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Affiliation(s)
- Hon Wai Koon
- Center for Inflammatory Bowel Diseases, Vatche and Tamar Manoukian Division of Digestive Diseases, David Geffen School of Medicine at the University of California, Los Angeles, Los Angeles, California, USA
| | - Jiani Wang
- Center for Inflammatory Bowel Diseases, Vatche and Tamar Manoukian Division of Digestive Diseases, David Geffen School of Medicine at the University of California, Los Angeles, Los Angeles, California, USA
- Department of Gastroenterology, First Affiliated Hospital, China Medical University, Shenyang City, Liaoning Province, China
| | - Caroline C Mussatto
- Center for Inflammatory Bowel Diseases, Vatche and Tamar Manoukian Division of Digestive Diseases, David Geffen School of Medicine at the University of California, Los Angeles, Los Angeles, California, USA
| | - Christina Ortiz
- Center for Inflammatory Bowel Diseases, Vatche and Tamar Manoukian Division of Digestive Diseases, David Geffen School of Medicine at the University of California, Los Angeles, Los Angeles, California, USA
| | - Elaine C Lee
- Center for Inflammatory Bowel Diseases, Vatche and Tamar Manoukian Division of Digestive Diseases, David Geffen School of Medicine at the University of California, Los Angeles, Los Angeles, California, USA
| | - Diana Hoang-Ngoc Tran
- Center for Inflammatory Bowel Diseases, Vatche and Tamar Manoukian Division of Digestive Diseases, David Geffen School of Medicine at the University of California, Los Angeles, Los Angeles, California, USA
| | - Xinhua Chen
- Division of Gastroenterology, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA
| | - Ciaran P Kelly
- Division of Gastroenterology, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA
| | - Charalabos Pothoulakis
- Center for Inflammatory Bowel Diseases, Vatche and Tamar Manoukian Division of Digestive Diseases, David Geffen School of Medicine at the University of California, Los Angeles, Los Angeles, California, USA
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10
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Koon HW, Su B, Xu C, Mussatto CC, Tran DHN, Lee EC, Ortiz C, Wang J, Lee JE, Ho S, Chen X, Kelly CP, Pothoulakis C. Probiotic Saccharomyces boulardii CNCM I-745 prevents outbreak-associated Clostridium difficile-associated cecal inflammation in hamsters. Am J Physiol Gastrointest Liver Physiol 2016; 311:G610-G623. [PMID: 27514478 PMCID: PMC5142203 DOI: 10.1152/ajpgi.00150.2016] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/15/2016] [Accepted: 07/29/2016] [Indexed: 01/31/2023]
Abstract
C. difficile infection (CDI) is a common debilitating nosocomial infection associated with high mortality. Several CDI outbreaks have been attributed to ribotypes 027, 017, and 078. Clinical and experimental evidence indicates that the nonpathogenic yeast Saccharomyces boulardii CNCM I-745 (S.b) is effective for the prevention of CDI. However, there is no current evidence suggesting this probiotic can protect from CDI caused by outbreak-associated strains. We used established hamster models infected with outbreak-associated C. difficile strains to determine whether oral administration of live or heat-inactivated S.b can prevent cecal tissue damage and inflammation. Hamsters infected with C. difficile strain VPI10463 (ribotype 087) and outbreak-associated strains ribotype 017, 027, and 078 developed severe cecal inflammation with mucosal damage, neutrophil infiltration, edema, increased NF-κB phosphorylation, and increased proinflammatory cytokine TNFα protein expression. Oral gavage of live, but not heated, S.b starting 5 days before C. difficile infection significantly reduced cecal tissue damage, NF-κB phosphorylation, and TNFα protein expression caused by infection with all strains. Moreover, S.b-conditioned medium reduced cell rounding caused by filtered supernatants from all C. difficile strains. S.b-conditioned medium also inhibited toxin A- and B-mediated actin cytoskeleton disruption. S.b is effective in preventing C. difficile infection by outbreak-associated via inhibition of the cytotoxic effects of C. difficile toxins.
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Affiliation(s)
- Hon Wai Koon
- Inflammatory Bowel Disease Research Center, Division of Digestive Diseases, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California
| | - Bowei Su
- Inflammatory Bowel Disease Research Center, Division of Digestive Diseases, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California
| | - Chunlan Xu
- Inflammatory Bowel Disease Research Center, Division of Digestive Diseases, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California; The Key Laboratory for Space Bioscience and Biotechnology, School of Life Sciences, Northwestern Polytechnical University, Xi'an, Shaanxi, P.R. China
| | - Caroline C Mussatto
- Inflammatory Bowel Disease Research Center, Division of Digestive Diseases, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California
| | - Diana Hoang-Ngoc Tran
- Inflammatory Bowel Disease Research Center, Division of Digestive Diseases, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California
| | - Elaine C Lee
- Inflammatory Bowel Disease Research Center, Division of Digestive Diseases, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California
| | - Christina Ortiz
- Inflammatory Bowel Disease Research Center, Division of Digestive Diseases, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California
| | - Jiani Wang
- Inflammatory Bowel Disease Research Center, Division of Digestive Diseases, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California
| | - Jung Eun Lee
- Inflammatory Bowel Disease Research Center, Division of Digestive Diseases, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California
| | - Samantha Ho
- Inflammatory Bowel Disease Research Center, Division of Digestive Diseases, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California
| | - Xinhua Chen
- Division of Gastroenterology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts; and
| | - Ciaran P Kelly
- Division of Gastroenterology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts; and
| | - Charalabos Pothoulakis
- Inflammatory Bowel Disease Research Center, Division of Digestive Diseases, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California;
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11
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Girinathan BP, Braun S, Sirigireddy AR, Lopez JE, Govind R. Importance of Glutamate Dehydrogenase (GDH) in Clostridium difficile Colonization In Vivo. PLoS One 2016; 11:e0160107. [PMID: 27467167 PMCID: PMC4965041 DOI: 10.1371/journal.pone.0160107] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2016] [Accepted: 07/12/2016] [Indexed: 01/04/2023] Open
Abstract
Clostridium difficile is the principal cause of antibiotic-associated diarrhea. Major metabolic requirements for colonization and expansion of C. difficile after microbiota disturbance have not been fully determined. In this study, we show that glutamate utilization is important for C. difficile to establish itself in the animal gut. When the gluD gene, which codes for glutamate dehydrogenase (GDH), was disrupted, the mutant C. difficile was unable to colonize and cause disease in a hamster model. Further, from the complementation experiment it appears that extracellular GDH may be playing a role in promoting C. difficile colonization and disease progression. Quantification of free amino acids in the hamster gut during C. difficile infection showed that glutamate is among preferred amino acids utilized by C. difficile during its expansion. This study provides evidence of the importance of glutamate metabolism for C. difficile pathogenesis.
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Affiliation(s)
| | - Sterling Braun
- Division of Biology, Kansas State University, Manhattan, Kansas, 66502, United States of America
| | | | - Jose Espinola Lopez
- Division of Biology, Kansas State University, Manhattan, Kansas, 66502, United States of America
| | - Revathi Govind
- Division of Biology, Kansas State University, Manhattan, Kansas, 66502, United States of America
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12
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Zhang Y, Feng H. Pathogenic effects of glucosyltransferase from Clostridium difficile toxins. Pathog Dis 2016; 74:ftw024. [PMID: 27044305 DOI: 10.1093/femspd/ftw024] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 03/30/2016] [Indexed: 01/13/2023] Open
Abstract
The glucosyltransferase domain ofClostridium difficiletoxins modifies guanine nucleotide-binding proteins of Rho family. It is the major virulent domain of the holotoxins. Various pathogenic effects ofC. difficiletoxins in response to Rho glucosylation have been investigated including cytoskeleton damage, cell death and inflammation. The most recent studies have revealed some significant characteristics of the holotoxins that are independent of glucosylating activity. These findings arouse discussion about the role of glucosyltransferase activity in toxin pathogenesis and open up new insights for toxin mechanism study. In this review, we summarize the pathogenic effects of glucosyltransferase domain of the toxins in the past years.
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Affiliation(s)
- Yongrong Zhang
- Department of Microbial Pathogenesis, University of Maryland Baltimore, 650 W. Baltimore Street, Baltimore, MD 21201, USA
| | - Hanping Feng
- Department of Microbial Pathogenesis, University of Maryland Baltimore, 650 W. Baltimore Street, Baltimore, MD 21201, USA
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13
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Fidaxomicin: A novel agent for the treatment of Clostridium difficile infection. CANADIAN JOURNAL OF INFECTIOUS DISEASES & MEDICAL MICROBIOLOGY 2016; 26:305-12. [PMID: 26744587 PMCID: PMC4692299 DOI: 10.1155/2015/934594] [Citation(s) in RCA: 54] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 11/17/2022]
Abstract
Oral vancomycin and oral metronidazole have several limitations with regard to their use in the treatment of Clostridium difficile infections (CDIs); however, oral vancomycin has been considered the gold standard in clinical trials. In June 2012, fidaxomicin received Health Canada approval for the treatment of CDIs. Its chemistry, mechanisms of action and pharmacological properties are discussed, along with its potential role in CDI therapy. BACKGROUND: Due to the limitations of existing treatment options for Clostridium difficile infection (CDI), new therapies are needed. OBJECTIVE: To review the available data on fidaxomicin regarding chemistry, mechanisms of action and resistance, in vitro activity, pharmacokinetic and pharmacodynamic properties, efficacy and safety in clinical trials, and place in therapy. METHODS: A search of PubMed using the terms “fidaxomicin”, “OPT-80”, “PAR-101”, “OP-1118”, “difimicin”, “tiacumicin” and “lipiarmycin” was performed. All English-language articles from January 1983 to November 2014 were reviewed, as well as bibliographies of all articles. RESULTS: Fidaxomicin is the first macrocyclic lactone antibiotic with activity versus C difficile. It inhibits RNA polymerase, therefore, preventing transcription. Fidaxomicin (and its active metabolite OP-1118) is bactericidal against C difficile and exhibits a prolonged postantibiotic effect (approximately 10 h). Other than for C difficile, fidaxomicin demonstrated only moderate inhibitory activity against Gram-positive bacteria and was a poor inhibitor of normal colonic flora, including anaerobes and enteric Gram-negative bacilli. After oral administration (200 mg two times per day for 10 days), fidaxomicin achieved low serum concentration levels but high fecal concentration levels (mean approximately 1400 μg/g stool). Phase 3 clinical trials involving adults with CDI demonstrated that 200 mg fidaxomicin twice daily for 10 days was noninferior to 125 mg oral vancomycin four times daily for 10 days in regard to clinical response at the end of therapy. Fidaxomicin was, however, reported to be superior to oral vancomycin in reducing recurrent CDI and achieving a sustained clinical response (assessed at day 28) for patients infected with non-BI/NAP1/027 strains. CONCLUSION: Fidaxomicin was noninferior to oral vancomycin with regard to clinical response at the end of CDI therapy. Fidaxomicin has been demonstated to be as safe as oral vancomycin, but superior to vancomycin in achieving a sustained clinical response for CDI in patients infected with non-BI/NAP1/027 strains. Caution should be exercised in using fidaxomicin monotherapy for treatment of severe complicated CDI because limited data are available. Whether fidaxomicin is cost effective (due to its significantly higher acquisition cost versus oral vancomycin) depends on the acceptable willingness to pay threshold per quality-adjusted life year as a measure of assessing cost effectiveness.
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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.
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Affiliation(s)
- David Padua
- a Department of Medicine , University of California, Los Angeles , Los Angeles , CA , USA
| | - Charalabos Pothoulakis
- a Department of Medicine , University of California, Los Angeles , Los Angeles , CA , USA
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15
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Shields K, Araujo-Castillo RV, Theethira TG, Alonso CD, Kelly CP. Recurrent Clostridium difficile infection: From colonization to cure. Anaerobe 2015; 34:59-73. [PMID: 25930686 PMCID: PMC4492812 DOI: 10.1016/j.anaerobe.2015.04.012] [Citation(s) in RCA: 75] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2015] [Revised: 04/22/2015] [Accepted: 04/23/2015] [Indexed: 12/16/2022]
Abstract
Clostridium difficile infection (CDI) is increasingly prevalent, dangerous and challenging to prevent and manage. Despite intense national and international attention the incidence of primary and of recurrent CDI (PCDI and RCDI, respectively) have risen rapidly throughout the past decade. Of major concern is the increase in cases of RCDI resulting in substantial morbidity, morality and economic burden. RCDI management remains challenging as there is no uniformly effective therapy, no firm consensus on optimal treatment, and reliable data regarding RCDI-specific treatment options is scant. Novel therapeutic strategies are critically needed to rapidly, accurately, and effectively identify and treat patients with, or at-risk for, RCDI. In this review we consider the factors implicated in the epidemiology, pathogenesis and clinical presentation of RCDI, evaluate current management options for RCDI and explore novel and emerging therapies.
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Affiliation(s)
- Kelsey Shields
- Division of Gastroenterology, Beth Israel Deaconess Medical Center, Harvard Medical School, 330 Brookline Ave., Boston, MA 02215, United States.
| | - Roger V Araujo-Castillo
- Division of Infectious Diseases, Beth Israel Deaconess Medical Center, Harvard Medical School, Lowry Medical Office Building, Suite GB 110 Francis Street, Boston, MA 02215, United States.
| | - Thimmaiah G Theethira
- Division of Gastroenterology, Beth Israel Deaconess Medical Center, Harvard Medical School, 330 Brookline Ave., Boston, MA 02215, United States.
| | - Carolyn D Alonso
- Division of Infectious Diseases, Beth Israel Deaconess Medical Center, Harvard Medical School, Lowry Medical Office Building, Suite GB 110 Francis Street, Boston, MA 02215, United States.
| | - Ciaran P Kelly
- Division of Gastroenterology, Beth Israel Deaconess Medical Center, Harvard Medical School, 330 Brookline Ave., Boston, MA 02215, United States.
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16
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Mathur H, Rea MC, Cotter PD, Ross RP, Hill C. The potential for emerging therapeutic options for Clostridium difficile infection. Gut Microbes 2015; 5:696-710. [PMID: 25564777 PMCID: PMC4615897 DOI: 10.4161/19490976.2014.983768] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/03/2023] Open
Abstract
Clostridium difficile is mainly a nosocomial pathogen and is a significant cause of antibiotic-associated diarrhea. It is also implicated in the majority of cases of pseudomembranous colitis. Recently, advancements in next generation sequencing technology (NGS) have highlighted the extent of damage to the gut microbiota caused by broad-spectrum antibiotics, often resulting in C. difficile infection (CDI). Currently the treatment of choice for CDI involves the use of metronidazole and vancomycin. However, recurrence and relapse of CDI, even after rounds of metronidazole/vancomycin administration is a problem that must be addressed. The efficacy of alternative antibiotics such as fidaxomicin, rifaximin, nitazoxanide, ramoplanin and tigecycline, as well as faecal microbiota transplantation has been assessed and some have yielded positive outcomes against C. difficile. Some bacteriocins have also shown promising effects against C. difficile in recent years. In light of this, the potential for emerging treatment options and efficacy of anti-C. difficile vaccines are discussed in this review.
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Key Words
- ATCC, American Type Culture Collection
- CDI, Clostridium difficile infection
- CdtLoc, binary toxin locus
- Clostridium difficile
- DNA, deoxyribonucleic acid
- DPC, Dairy Products Collection
- ESCMID, European Society of Clinical Microbiology and Infectious Diseases
- ETEC, enterotoxigenic E. coli
- FDA, Food and Drug Administration
- FMT, faecal microbiota transplantation
- GIT, gastrointestinal tract
- HIV, human immunodeficiency virus
- IDSA, Infectious Diseases Society of America
- IgG, immunoglobulin G
- LTA, lipoteichoic acid
- M21V, methionine to valine substitution at residue 21
- MIC, minimum inhibitory concentration
- NGS, next generation sequencing
- NVB, Novacta Biosystems Ltd
- PMC, pseudomembranous colitis
- PaLoc, pathogenicity locus
- R027, ribotype 027
- RBD
- RBS, ribosome binding site
- RNA, ribonucleic acid
- SHEA, Society for Healthcare Epidemiology of America
- V15F, valine to phenylalanine substitution at residue 15
- antibiotics
- faecal microbiota transplantation
- receptor binding domain
- toxins
- vaccines
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Affiliation(s)
- Harsh Mathur
- School of Microbiology; University College Cork; Cork, Ireland,Teagasc Food Research Center; Moorepark; Fermoy, Ireland
| | - Mary C Rea
- Teagasc Food Research Center; Moorepark; Fermoy, Ireland,Alimentary Pharmabiotic Center; University College Cork; Cork, Ireland
| | - Paul D Cotter
- Teagasc Food Research Center; Moorepark; Fermoy, Ireland,Alimentary Pharmabiotic Center; University College Cork; Cork, Ireland,Correspondence to: Colin Hill; ; Paul D Cotter;
| | - R Paul Ross
- Alimentary Pharmabiotic Center; University College Cork; Cork, Ireland,College of Science; Engineering and Food Science; University College Cork; Cork, Ireland
| | - Colin Hill
- School of Microbiology; University College Cork; Cork, Ireland,Alimentary Pharmabiotic Center; University College Cork; Cork, Ireland,Correspondence to: Colin Hill; ; Paul D Cotter;
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