Materiały źródłowe

• #1 Pseudomembranous Colitis

  https://pmc.ncbi.nlm.nih.gov/articles/PMC4402243/

  Pseudomembranous colitis is an inflammatory condition of the colon characterized by elevated yellow-white plaques that coalesce to form pseudomembranes on the mucosa. […] The pathophysiology of CDI has been studied extensively and appears to progress in a particular sequence. The common first step is the disruption of the normal colonic flora with subsequent C. difficile colonization. […] Following initial colonization, clinically significant infection is mediated by toxin production. Most disease-causing strains produce two large protein exotoxins, toxin A and toxin B. […] Inside the cell, they cause glycosylation of small proteins involved in cell signaling and regulating pathways. This, in turn, leads to cytoskeleton disruption, causing cell morphologic changes, cytokine activation, and eventual cell death.

• #1 Pseudomembranous colitis: Not always Clostridium difficile | Cleveland Clinic Journal of Medicine

  https://www.ccjm.org/content/83/5/361

  Although Clostridium difficile infection is the cause of most cases of pseudomembranous colitis, clinicians should consider less common causes, especially if pseudomembranes are seen on endoscopy but testing remains negative for C difficile or if presumed C difficile infection does not respond to treatment. Histologic review of colonic mucosal biopsy specimens can provide clues to the underlying cause. […] Pseudomembranous colitis is a nonspecific pattern of injury resulting from decreased oxygenation, endothelial damage, and impaired blood flow to the mucosa that can be triggered by a number of disease states. […] Chemicals, medications, ischemia, microscopic colitis, other infectious organisms, and inflammatory conditions can all predispose to pseudomembrane formation and should be included in the differential diagnosis.

• #1 Pseudomembranous Colitis: What It Is, Symptoms, Causes, Treatment

  https://my.clevelandclinic.org/health/diseases/17718-pseudomembranous-colitis

  Pseudomembranous colitis (PMC) is a severe form of colitis. In this condition, something attacks and injures your colon lining (mucosa). It might be bacteria, toxins or another illness. Your colon mucosa develops thickened, scab-like plaques over the wounds. Your healthcare provider might call these pseudomembranes. […] C. difficile produces toxins that injure your colon mucosa, causing cell death. C. diff infection also can become unusually severe, unusually fast. C. diff infection usually happens after you’ve taken antibiotics. Antibiotics reduce the other bacteria in your gut, but they don’t affect C. diff. This allows C. diff to quickly grow out of control. […] Other causes of colitis can also lead to pseudomembranous colitis, including: Staphylococcus aureus infection, E. coli infection, Cytomegalovirus infection, Microscopic colitis, Behets disease, Ischemic colitis, Chemotherapy drugs, Cocaine use, Vasculitis, Heavy metal poisoning. In these cases, colitis is more severe or more complicated than usual. Complications can include reduced blood flow to your colon mucosa (ischemia), which can lead to tissue death and pseudomembranes. Preexisting conditions like inflammatory bowel disease (IBD) may also make your colon more vulnerable. […] If C. diff infection is the cause of your pseudomembranous colitis, there are a few drugs that can treat it. Your provider will choose the best one for you. Drugs to treat C. diff infection include: Metronidazole, Vancomycin, Fidaxomicin.

• #1 Clostridioides (Clostridium) Difficile Colitis: Background, Etiology, Pathophysiology

  https://emedicine.medscape.com/article/186458-overview

  Clostridioides difficile (formerly Clostridium difficile) is a gram-positive, anaerobic, spore-forming bacillus that is responsible for the development of antibiotic-associated diarrhea and colitis. C difficile colitis results from a disturbance of the normal bacterial flora of the colon, colonization by C difficile, and the release of toxins that cause mucosal inflammation and damage. […] C difficile colitis results from a disruption of the normal bacterial flora of the colon, colonization with C difficile, and release of toxins that cause mucosal inflammation, mucosal damage, and diarrhea. […] C difficile forms heat-resistant spores that can persist in the environment for several months to years. Outbreaks of C difficile diarrhea may occur in hospitals and outpatient facilities where contamination with spores is prevalent. Although the normal gut flora resists colonization and overgrowth with C difficile, the use of antibiotics, which alter and suppress the normal flora, allows proliferation of C difficile, toxin production, and diarrhea.

• #1 Clostridioides (formerly Clostridium) difficile–Induced Diarrhea – Infectious Diseases – MSD Manual Professional Edition

  https://www.msdmanuals.com/professional/infectious-diseases/anaerobic-bacteria/clostridioides-formerly-clostridium-difficile-induced-diarrhea

  Toxins produced by Clostridioides difficile strains in the gastrointestinal tract cause pseudomembranous colitis, typically after antibiotic use. […] The organism secretes both an enterotoxin and a cytotoxin, typically referred to as toxins A and B. […] The main effect of the toxin is on the colon, which secretes fluid and develops characteristic pseudomembranes discrete yellow-white plaques that are easily dislodged. […] Antibiotic-induced changes in gastrointestinal flora are the dominant predisposing factors. […] Cephalosporins (particularly 3rd-generation), penicillins, clindamycin, and fluoroquinolones pose the highest risk. […] Antibiotic therapy can cause intestinal overgrowth of toxin-secreting C. difficile, resulting in a pseudomembranous colitis that can be severe and difficult to cure.

• #1 Pseudomembranous Colitis | Concise Medical Knowledge

  https://www.lecturio.com/concepts/pseudomembranous-colitis/

  2%3% of healthy adults are colonized with C. difficile. […] Disruption of the normal flora using antibiotics leads to the overgrowth of C. difficile. […] Intestinal damage is due to toxin release. […] Toxins released by C. difficile: Enterotoxin A targets brush-border enzymes, alters fluid secretion, and causes watery diarrhea. […] Toxin B (10 times more potent) depolymerizes actin, disrupts cytoskeleton of enterocytes, and causes pseudomembranous colitis.

• #1 11. Pseudomembranous Colitis Images | PPT

  https://www.slideshare.net/ensteve/11-pseudomembranous-colitis-images

  Most cases of PMC over the last three decades have occurred in association with antimicrobial therapy. Nearly all antimicrobial agents have been implicated in causing PMC. […] Broad spectrum antibiotic usage (such as clindamycin) and/or immunosuppression allows overgrowth of bacteria such as Clostridium difficile. […] Pathophysiology disruption of the normal bacterial flora of the colon colonization with C. difficile release of toxins mucosal damage and inflammation. […] Toxin production by pathogens toxin A (or enterotoxin) toxin B (or cytotoxin). Both are heat-labile proteins that activate the release of cytokines from human monocytes. […] Toxins are released by C.difficile and internalised by endocystosis. […] Both toxins activate phospholipase A2 leading to calcium influx and the production of arachidonic acid metabolites.

• #1 Pathology Outlines – Pseudomembranous colitis

  https://www.pathologyoutlines.com/topic/colonaacolitis.html

  Pseudomembranous formation occurs by toxin activation of the native immune system and by activation of macrophages and monocytes, leading to release of proinflammatory cytokines like interleukin 1, interleukin 8, tumor necrosis factor and leukotriene B4 (Dis Mon 2015;61:181) […] For cases caused by C. difficile, usage of other antibiotics disrupts normal gut flora, allowing C. difficile to establish a presence. After colonization, the bacteria produce 2 large exoproteins, toxins A and B. Following release in the colon, the toxins bind to cell surface receptors and are internalized into the cell. Glycosylation of small proteins occurs inside the cells involved in signaling and regulating pathways. Leads to cytoskeleton disruption, causing morphologic cell changes, cytoskeleton activation and cell death. Infiltration of neutrophils and inflammatory cell reaction occurs due to tight junctions getting affected.

• #1 Conference 3 – 2016  &nbsp Case: 4     &nbsp 20160907

  https://www.askjpc.org/wsco/wsc_showcase2.php?id=VjFJdW1qaU9wQnVZMzFqckYzcHBHdz09

  The gross and microscopic findings in this case are consistent with Clostridium difficile colitis, also referred to as C. difficile-associated disease (CDAD). […] C. difficile is recognized as one of the most important nosocomial pathogens in humans, causing illness ranging from mild diarrhea to fulminant colitis. […] The disease has been well characterized histologically, occurring in three stages: 1) focal epithelial necrosis along with fibrin-rich exudates, 2) marked exudation protruding through an area of mucosal ulceration (characterized as classical volcano lesions), and 3) diffuse, more severe mucosal ulceration with necrosis and associated pseudomembrane composed of fibrin, leukocytes and cellular debris. […] C. difficile infection occurs when the natural flora in the gut is disrupted.

• #1 Pseudomembranous colitis: Not always Clostridium difficile | Cleveland Clinic Journal of Medicine

  https://www.ccjm.org/content/83/5/361

  Pseudomembranous colitis is most often due to Clostridium difficile infection, but it has a variety of other causes, including other infections, ischemia, medications, and inflammatory mucosal diseases. […] When pseudomembranes are found, one should consider these other causes if tests for C difficile are negative or if anti-C difficile therapy does not produce a response. […] Pseudomembranous colitis is a nonspecific finding that suggests a larger disease process. […] Associated signs and symptoms, including fever, abdominal pain, leukocytosis, diarrhea, toxic megacolon, and electrolyte imbalances, may portend a life-threatening condition. […] A pseudomembrane is a layer of fibropurulent exudate composed of acute inflammatory cells and mucus originating from inflamed and erupting crypts.

• #1 Apoptosis of intestinal epithelial cells restricts Clostridium difficile infection in a model of pseudomembranous colitis | Nature Communications

  https://www.nature.com/articles/s41467-018-07386-5

  We found that unlike in myeloid cells, the Pyrin inflammasome is not functional in IECs and that the central pyroptosis effector GSDMD is dispensable for C. difficile toxin-induced IEC killing. […] Instead, we identified C. difficile toxin-induced activation of the apoptotic executioner proteases caspases 3 and 7 by the intrinsic apoptosis pathway as a critical mechanism driving IEC death. […] Collectively, these results establish that apoptotic executioner caspases 3 and 7 are critical for C. difficile-induced IEC cytotoxicity. […] In conclusion, these results exclude a role for death receptor-induced apoptosis and necroptosis signaling in C. difficile toxin-induced IEC cytotoxicity, and suggest that mechanisms redundant to the pro-apoptotic Bax/Bak pore that lead to mitochondrial outer membrane permeabilization (MOMP) may promote TcdA/B-induced caspase-3/7 activation and IEC apoptosis through the intrinsic apoptosis pathway.

• #1 Apoptosis of intestinal epithelial cells restricts Clostridium difficile infection in a model of pseudomembranous colitis | Nature Communications

  https://www.nature.com/articles/s41467-018-07386-5

  Clostridium difficile is the leading cause of pseudomembranous colitis in hospitalized patients. C. difficile enterotoxins TcdA and TcdB promote this inflammatory condition via a cytotoxic response on intestinal epithelial cells (IECs), but the underlying mechanisms are incompletely understood. […] Here we show that the Pyrin inflammasome is not functional in IECs and that Pyrin signaling is dispensable for CDI-associated IEC death and for in vivo pathogenesis. Instead, our studies establish that C. difficile enterotoxins induce activation of executioner caspases 3/7 via the intrinsic apoptosis pathway, and demonstrate that caspase-3/7-mediated IEC apoptosis is critical for in vivo host defense during early stages of CDI. In conclusion, our findings dismiss a critical role for inflammasomes in CDI pathogenesis, and identify IEC apoptosis as a host defense mechanism that restricts C. difficile infection in vivo.

• #1 Pseudomembranous colitis – Symptoms & causes – Mayo Clinic

  https://www.mayoclinic.org/diseases-conditions/pseudomembranous-colitis/symptoms-causes/syc-20351434

  Pseudomembranous colitis occurs when certain bacteria, usually C. difficile, rapidly outgrow other bacteria that typically keep them in check. […] Certain toxins produced by C. difficile can rise to levels high enough to damage the colon. […] An aggressive strain of C. difficile has emerged that produces far more toxins than other strains do. The new strain may be more resistant to certain medicines and has been reported in people who haven’t been in the hospital or taken antibiotics.

• #1 Exploring the Toxin-Mediated Mechanisms in Clostridioides difficile Infection

  https://www.mdpi.com/2076-2607/12/5/1004

  Recent findings indicate that TcdB is more closely associated with CDI severity, supported by clinical strains predominantly producing TcdB and strains lacking TcdA but causing severe disease. […] These toxins are pivotal in CDI pathogenesis, disrupting cell adhesion, and cytoskeletal rearrangements, and triggering pro-inflammatory responses and cell death. […] The endocytosis and release of TcdA and TcdB into the cytosol of the host cell can be distinguished into five stages: (i) binding of the toxins to cell surface receptors; (ii) cellular uptake via endocytosis; (iii) formation of pores in endosomal membrane; (iv) translocation of the toxin into the cytosol; (v) glycosylation of Rho/Ras GTPases; and (vi) cellular impacts. […] Once GTD is released into the cytosol, it selectively transfers UDP-glucose to Rho and Ras proteins, leading to their inactivation.

• #1 Pseudomembranous Colitis

  https://pmc.ncbi.nlm.nih.gov/articles/PMC4402243/

  Pseudomembranes form via this influx of neutrophils into the mucosa and further activation of the native immune system by the toxins. […] The pathogenesis underlying the worse prognosis in IRCI is not clear; it has been postulated that the right colon, typically supplied by the SMA, is more sensitive to non-occlusive ischemia, as there is little collateral circulation and the vasa recta that supply the right colon initiate closer to the left colon and have to travel further to reach the right side. […] Ischemia as a cause of PMC is not a novel concept, but it is often not recognized early in the course of disease, owing to the strong association of pseudomembranes with CDI.

• #1 Pseudomembranous colitis: Not always Clostridium difficile | MDedge

  https://medauth2.mdedge.com/content/pseudomembranous-colitis-not-always-clostridium-difficile

  Microvascular thrombosis is the likely mechanism in a number of non-C difficile causes of pseudomembranous colitis. […] In most patients with enterohemorrhagic E coli O157:H7 infection, histologic review of colonic mucosal biopsies has revealed fibrin and platelet thrombi in the capillaries, suggesting microvascular thrombosis. […] Cocaine has been associated with pseudomembranes in the setting of ischemia in the cecum and ascending colon. […] Pseudomembranous colitis can occur in Behet disease in the absence of C difficile infection or any infectious colitis. […] Pseudomembranes can be found on endoscopy in patients with inflammatory bowel disease during a disease exacerbation with or without C difficile. […] Pseudomembranous colitis has been reported in a patient with ulcerative colitis exacerbation in association with cytomegalovirus colitis.

• #1 Pseudomembranous colitis: Not always Clostridium difficile | Cleveland Clinic Journal of Medicine

  https://www.ccjm.org/content/83/5/361

  Colon ischemia usually affects elderly or debilitated patients who have multiple comorbidities. […] The ischemia can be related to an occlusive arterial or venous thromboembolism, but hypoperfusion without occlusion of the mesenteric or internal iliac arteries is the primary mechanism. […] Inflammatory bowel disease. Crohn disease and ulcerative colitis have been associated with pseudomembranous colitis. […] Pseudomembranes can be found on endoscopy in patients with inflammatory bowel disease during a disease exacerbation with or without C difficile.

• #1 Pseudomembranous colitis: Not always Clostridium difficile | MDedge

  https://medauth2.mdedge.com/content/pseudomembranous-colitis-not-always-clostridium-difficile

  Although most often seen in C difficile infection, pseudomembranous colitis is a nonspecific pattern of injury resulting from decreased oxygenation, endothelial damage, and impaired blood flow to the mucosa that can be triggered by a number of disease states. […] When pseudomembranous colitis is confirmed endoscopically, C difficile infection naturally comes to mind, but the two terms are not interchangeable. […] Several chemicals and medications can injure the bowel and predispose to pseudomembrane formation. […] Chemotherapeutic and antiproliferative agents can be toxic to the bowel, generally through production of free radicals and up-regulation of inflammatory cytokines. […] The colonic epithelium is then more susceptible to ulceration and mucosal necrosis with pseudomembrane development.

• #1 Pathogenesis of Clostridium difficile-associated diarrhoea – PubMed

  https://pubmed.ncbi.nlm.nih.gov/8944363/

  Clostridium difficile is now regarded as a major enteric pathogen in hospitals and nursing-home facilities. The pathophysiology of this pathogen involves alterations of the indigenous colonic flora by antibiotics, ingestion of spores and colonization by C. difficile, followed by release of its toxins. […] An important characteristic of C. difficile infection is the dramatic inflammation seen in pseudomembranous colitis. Recent studies indicate that an interplay between lamina propria neuroimmune cells and intestinal epithelial cells may be central in pathogenesis of this toxin-mediated inflammatory response.

• #1 Clostridioides (Clostridium) Difficile Colitis: Background, Etiology, Pathophysiology

  https://emedicine.medscape.com/article/186458-overview

  The NAP1 hypervirulent strain of C difficile is associated with the most serious sequelae of CDI, causing severe and fulminant colitis that is characterized by leukocytosis, renal failure, and toxic megacolon. […] The overall suggestion from this study is that the substance P receptor is very important in the pathogenesis of inflammatory diarrhea. […] Further insight into the genetics of C difficile toxin A reveals that the main binding protein is gp96. In addition, it has been found that C difficile has potent stimulatory activity for the Nod1 gene, and mice who were homozygous knockouts for Nod1 had increased lethality to CDI despite similar levels of intestinal damage relative to control the mice. The implication of this study is that Nod1 regulates the susceptibility to C difficile. […] Ultimately, many of the genetic influences on CDI and the clinical course of C difficile colitis likely remain unknown. At this point, it is understood that subtle differences in the immune system may significantly influence the natural history of C difficile disease.

• #1 Colonoscopy Finding: Pseudomembranous Colitis in Chronic Kidney Disease Patient | Bioscientia Medicina : Journal of Biomedicine and Translational Research

  https://bioscmed.com/index.php/bsm/article/view/996

  Pseudomembranous colitis is a manifestation of severe colonic disease that is usually associated with Clostridium difficile infection but can be caused by a number of different etiologies. […] Pseudomembranous colitis occurs when changes in the fecal flora allow Clostridium difficile overgrowth. […] Gut dysbiosis, an alteration of the composition and function of gut microorganisms, is commonly seen in patients with chronic kidney disease. […] Pseudomembranous colitis is an inflammatory bowel condition most commonly caused by Clostridium difficile infection. The presence of pseudomembranous visualization in colonoscopy can significantly establish the diagnosis.

• #1 Basic and Clinical Aspects of Clostridium Difficile Colitis

  http://www.scielo.org.pe/scielo.php?script=sci_arttext&pid=S1022-51292004000300008

  C. difficile colitis has been shown to develop in patients taking antibiotics; however, neither the number of antibiotics nor the duration of therapy was a factor in predisposing patients to infection. […] Infection occurs via the fecal-oral route. The spores resist stomach acid and develop into a vegetative form in the colon. C. difficile toxins bind to specific receptors to stimulate fluid secretion and necrosis of the mucosa associated with an inflammatory infiltrate. […] C. difficile can colonize the bowel after a disturbance of the ecology of the intestinal flora. The oral inoculation of hamsters with small doses of C. difficile is sufficient to cause colitis after treatment with antibiotics. This fact suggests that certain organisms in the normal flora prevent colonization by C. difficile. Presumably, some components of the normal intestinal flora, such as lactobacilli and bacteroides, suppress the growth or prevent the colonization of C. difficile, and antibiotics confer a predisposition to disease by inhibiting these competing organisms.

• #1 Exploring the Toxin-Mediated Mechanisms in Clostridioides difficile Infection

  https://www.mdpi.com/2076-2607/12/5/1004

  TcdA and TcdB induce the release of inflammatory mediators from colonic epithelial cells, including interleukin-8 (IL-8) and interleukin-1 beta (IL-1β), correlating with CDI severity. […] TcdA and TcdB can breach the intestinal barrier and enter the bloodstream, resulting in systemic toxemia. […] Elevated levels of these toxins in the bloodstream can cause damage outside the colon, leading to dysfunction in multiple organs such as the heart, thymus, kidneys, and brain. […] The production of CDT has also been correlated with increased antibiotic resistance, and the detection of its gene could be used as a marker for antimicrobial susceptibility.

• #1 Pseudomembranous Colitis Surgery: Practice Essentials, Pathophysiology, Etiology

  https://emedicine.medscape.com/article/193031-overview

  Pseudomembranous colitis is an inflammatory disease of the colon. […] The antibiotic-induced change in the balance of normal gut flora allows overgrowth of C difficile. […] Colitis results from the bacterial production of large amount of toxins. The most important toxins are toxin A (enterotoxin) and toxin B (cytotoxin). […] The toxins bind to the mucosa, attack the membranes and the microfilaments of the mucosal cells, and subsequently result in cytoplasmic contraction, hemorrhage, inflammation, cellular necrosis, and protein loss. […] They also interfere with mucosal protein synthesis, stimulate granulocyte chemotaxis, and increase capillary permeability, intestinal myoelectric responses, and peristalsis. […] Intestinal tissue invasion by C difficile has been reported in fatal cases of pseudomembranous colitis in pediatric patients with hematologic malignancy.

• #1 A Case Report of Pseudomembranous Colitis Resulting from Clostridium difficile Infection Successfully Treated with Fidaxomicin | Cardoso | Journal of Medical Cases

  https://www.journalmc.org/index.php/JMC/article/view/2632/1988

  New drugs have emerged for the treatment of CDI, including fidaxomicin, a macrocyclic antibiotic, the first in its class. Fidaxomicin acts by inhibiting C. difficile’s RNA polymerase, causing C. difficile cell death and presents selective bactericidal activity against C. difficile, which is in contrast to vancomycin that is only bacteriostatic against this agent. […] According to the European Society of Clinical Microbiology and Infectious Diseases (ESCMID) guidelines, recurrence is the major challenge in the treatment of CDI, with up to 25% of patients with CDI suffering a recurrence of infection within 30 days after treatment with metronidazole or vancomycin and 45-65% of these patients present subsequent recurrences. […] Fidaxomicin inhibits spore formation and toxin production by C. difficile. It acts locally and has no cross-resistance with currently available antibacterial agents. According to the results of phase III trials, this drug not only showed comparable efficacy with vancomycin in the treatment of CDI, but also showed superior efficacy in reducing disease recurrence, providing a sustained clinical cure.

• #1 Pseudomembranous colitis: MedlinePlus Medical EncyclopediaLock

  https://medlineplus.gov/ency/article/000259.htm

  Pseudomembranous colitis refers to swelling or inflammation of the large intestine (colon) due to an overgrowth of Clostridioides difficile (C difficile) bacteria. […] The bacteria give off a strong toxin that causes inflammation and bleeding in the lining of the colon. […] Any antibiotic can cause this condition. The medicines responsible for the problem most of the time are ampicillin, clindamycin, fluoroquinolones, and cephalosporins. […] Pseudomembranous colitis is uncommon in children, and rare in infants. It is most often seen in people who are in the hospital. However, it is becoming more common in people who take antibiotics and are not in a hospital. […] Long term antibiotics may be needed if the C difficile infection returns. A treatment called fecal microbiota transplant („stool transplant”) has also been effective for infections that come back. […] An antibody treatment may be needed in patients with very high risk of recurrent C difficile to lessen the risk of recurrence.

• #2 Non-clostridium difficile induced pseudomembranous colitis

  https://www.wjgnet.com/2307-8960/full/v11/i5/979.htm

  Pseudomembranous colitis is severe inflammation of the inner lining of the colon due to anoxia, ischemia, endothelial damage, and toxin production. […] The majority of cases of pseudomembranous colitis are due to Clostridium difficile. However, other causative pathogens and agents have been responsible for causing a similar pattern of injury to the bowel with the endoscopic appearance of yellow-white plaques and membranes on the mucosal surface of the colon. […] Pseudomembranous colitis is an acute inflammation of the colon. It is primarily due to the overgrowth of the bacterium clostridium difficile and the production of toxins that damage the colonic mucosa. […] Toxin A (Enterotoxin) and Toxin B (Cytotoxin) are the causative agents for triggering the immune system and leading to inflammation in the colon.

• #2 Clostridioides (Clostridium) Difficile Colitis: Background, Etiology, Pathophysiology

  https://emedicine.medscape.com/article/186458-overview

  Clostridioides difficile (formerly Clostridium difficile) is a gram-positive, anaerobic, spore-forming bacillus that is responsible for the development of antibiotic-associated diarrhea and colitis. C difficile colitis results from a disturbance of the normal bacterial flora of the colon, colonization by C difficile, and the release of toxins that cause mucosal inflammation and damage. […] C difficile colitis results from a disruption of the normal bacterial flora of the colon, colonization with C difficile, and release of toxins that cause mucosal inflammation, mucosal damage, and diarrhea. […] C difficile forms heat-resistant spores that can persist in the environment for several months to years. Outbreaks of C difficile diarrhea may occur in hospitals and outpatient facilities where contamination with spores is prevalent. Although the normal gut flora resists colonization and overgrowth with C difficile, the use of antibiotics, which alter and suppress the normal flora, allows proliferation of C difficile, toxin production, and diarrhea.

• #2 Conference 3 – 2016  &nbsp Case: 4     &nbsp 20160907

  https://www.askjpc.org/wsco/wsc_showcase2.php?id=VjFJdW1qaU9wQnVZMzFqckYzcHBHdz09

  After oral ingestion, spores, which are resistant to the acidity of the stomach, germinate into the vegetative form in the small intestine, leading to toxin production resulting in colitis. […] Both toxins, TcdA and TcdB, are cytotoxic, causing disruption of the actin cytoskeleton and tight junctions, resulting in decreased transepithelial resistance, fluid accumulation and destruction of the intestinal epithelium. […] The contributor provides an outstanding review of general information, diagnosis, pathogenesis, gross and microscopic lesions, and epidemiology of pseudomembranous colitis caused by Clostridium difficile across many species. […] C. difficile elaborates A and B toxins which diffuse into the tissue from the lumen and destroy the apical mucosal epithelium, in addition to causing the marked submucosal edema demonstrated in this case. […] Necrosis of the deeper mucosal surface and the colonic tunica muscularis has been reported in chronic cases.

• #2 Pseudomembranous colitis: MedlinePlus Medical EncyclopediaLock

  https://medlineplus.gov/ency/article/000259.htm

  Pseudomembranous colitis refers to swelling or inflammation of the large intestine (colon) due to an overgrowth of Clostridioides difficile (C difficile) bacteria. […] The bacteria give off a strong toxin that causes inflammation and bleeding in the lining of the colon. […] Any antibiotic can cause this condition. The medicines responsible for the problem most of the time are ampicillin, clindamycin, fluoroquinolones, and cephalosporins. […] Pseudomembranous colitis is uncommon in children, and rare in infants. It is most often seen in people who are in the hospital. However, it is becoming more common in people who take antibiotics and are not in a hospital. […] Long term antibiotics may be needed if the C difficile infection returns. A treatment called fecal microbiota transplant („stool transplant”) has also been effective for infections that come back. […] An antibody treatment may be needed in patients with very high risk of recurrent C difficile to lessen the risk of recurrence.

• #2 Pseudomembranous colitis – Symptoms & causes – Mayo Clinic

  https://www.mayoclinic.org/diseases-conditions/pseudomembranous-colitis/symptoms-causes/syc-20351434

  Pseudomembranous colitis occurs when certain bacteria, usually C. difficile, rapidly outgrow other bacteria that typically keep them in check. […] Certain toxins produced by C. difficile can rise to levels high enough to damage the colon. […] An aggressive strain of C. difficile has emerged that produces far more toxins than other strains do. The new strain may be more resistant to certain medicines and has been reported in people who haven’t been in the hospital or taken antibiotics.

• #2 Clostridioides (Clostridium) Difficile Colitis: Background, Etiology, Pathophysiology

  https://emedicine.medscape.com/article/186458-overview

  Pathogenic strains of C difficile produce two distinct toxins. Toxin A is an enterotoxin, and toxin B is a cytotoxin; both are high molecular weight proteins capable of binding to specific receptors on the intestinal mucosal cells. Receptor-bound toxins gain intracellular entry by catalyzing a specific alteration of Rho proteins small glutamyl transpeptidase (GTP) binding proteins that assist in actin polymerization, cytoskeletal architecture, and cell movement. Both toxin A and toxin B appear to play a role in the pathogenesis of C difficile colitis in humans. […] More recently, rat studies suggest that C difficile toxin B induces senescence in enteric glial cells (EGCs); investigators hypothesize that EGCs that survive toxin B and acquire senescence potentially cause the development of irritable bowel syndrome and inflammatory bowel disease via persistent inflammation, transfer of senescence status, and stimulation of preneoplastic cells.

• #2 Clostridioides difficile infection – Knowledge @ AMBOSS

  https://www.amboss.com/us/knowledge/clostridioides-difficile-infection/

  C. difficile possesses a range of virulence factors, the most important of which are toxins A and B. […] The C. difficile strain must be toxigenic to cause the disease. Intestinal colonization by nontoxigenic strains will result in asymptomatic carriage. […] Toxin A (enterotoxin) mechanism of action: binding to brush border of enterocytes: receptor-mediated endocytosis change of conformation exposure of active domain glycosylation of target proteins (e.g., Rac, Cdc42, RhoA) disruption of actin cytoskeleton functioning increase in epithelial permeability and apoptosis diarrhea. […] Toxin B (cytotoxin) mechanism of action: same as in toxin A, but can also cause pore formation within the endosomal membrane via insertion of the translocation domain release of endosomal content into the cytosol cytopathic effect.

• #2 11. Pseudomembranous Colitis Images | PPT

  https://www.slideshare.net/ensteve/11-pseudomembranous-colitis-images

  Prostaglandins and leukotrienes produce increased blood flow in local capillary beds and an increase in capillary permeability. […] Release of leukocytes, mucin, fibrin and cellular debris results in the formation of a pseudomembrane. […] In mild or moderate cases, supportive therapy alone is sufficient. […] Oral treatment with antimicrobial agents effective against C difficile is the preferred treatment. […] In severe cases, in cases where supportive therapy fails, and in cases where the offending antibiotic cannot be discontinued, a short course (7-10 d) of specific antibiotic therapy should be administered along with the supportive therapy. […] Surgical intervention is necessary for complications like toxic megacolon. […] Many patients remain asymptomatic carriers for C difficile, and most of them never relapse. […] The overall mortality rate is 2%. The mortality rate in untreated elderly or debilitated patients is 10-20%. Even with surgical intervention, the mortality rate in patients with toxic megacolon is 35%. […] Therapeutic strategies to inhibit toxin A-induced colitis are being tested.

• #2 Exploring the Toxin-Mediated Mechanisms in Clostridioides difficile Infection

  https://www.mdpi.com/2076-2607/12/5/1004

  The induction of glycosylation by toxins on Rho/Ras proteins, followed by the redistribution of the actin cytoskeleton, results in dramatic changes in cell morphology. […] TcdA and TcdB induce cell death (referred to as cytotoxic effect) in various cell types such as epithelial and endothelial cells, monocytes, lymphocytes, and neurons of the enteric nervous system within 18–48 h post-exposure. […] The deactivation of Rho GTPases leads to apoptosis, which occurs after the appearance of CPE. […] TcdB induces epithelial cell death via a bimodal mechanism dependent on toxin concentration. […] TcdA and TcdB stimulate various intracellular signaling pathways responsible for the production and release of inflammatory mediators. […] The inflammatory response observed in CDI originates from the effects of toxins on the intestinal epithelial cells and is primarily driven by the activation of the innate immune system.

• #2 Pathology Outlines – Pseudomembranous colitis

  https://www.pathologyoutlines.com/topic/colonaacolitis.html

  Pseudomembranous formation occurs by toxin activation of the native immune system and by activation of macrophages and monocytes, leading to release of proinflammatory cytokines like interleukin 1, interleukin 8, tumor necrosis factor and leukotriene B4 (Dis Mon 2015;61:181) […] For cases caused by C. difficile, usage of other antibiotics disrupts normal gut flora, allowing C. difficile to establish a presence. After colonization, the bacteria produce 2 large exoproteins, toxins A and B. Following release in the colon, the toxins bind to cell surface receptors and are internalized into the cell. Glycosylation of small proteins occurs inside the cells involved in signaling and regulating pathways. Leads to cytoskeleton disruption, causing morphologic cell changes, cytoskeleton activation and cell death. Infiltration of neutrophils and inflammatory cell reaction occurs due to tight junctions getting affected.

• #2 Pseudomembranous colitis: Not always Clostridium difficile | Cleveland Clinic Journal of Medicine

  https://www.ccjm.org/content/83/5/361

  Pseudomembranous colitis is most often due to Clostridium difficile infection, but it has a variety of other causes, including other infections, ischemia, medications, and inflammatory mucosal diseases. […] When pseudomembranes are found, one should consider these other causes if tests for C difficile are negative or if anti-C difficile therapy does not produce a response. […] Pseudomembranous colitis is a nonspecific finding that suggests a larger disease process. […] Associated signs and symptoms, including fever, abdominal pain, leukocytosis, diarrhea, toxic megacolon, and electrolyte imbalances, may portend a life-threatening condition. […] A pseudomembrane is a layer of fibropurulent exudate composed of acute inflammatory cells and mucus originating from inflamed and erupting crypts.

• #2 Basic and Clinical Aspects of Clostridium Difficile Colitis

  http://www.scielo.org.pe/scielo.php?script=sci_arttext&pid=S1022-51292004000300008

  Pseudomembranous colitis (PMC) was first recognized as a clinical entity in the 1950s. The advent of broad-spectrum antibiotics in the 1960s led to a marked rise in the numbers of PMC patients. It soon became clear that C. difficile could be isolated from the stools of PMC patients. PMC is the classical and dramatic manifestation of C. difficile infection. It is now accepted that C. difficile is responsible for virtually all antibiotic-associated colitis. […] The presence of pseudomembranes at endoscopy is diagnostic, but such presence can only be detected in about 50% of cases. The left colon is most commonly affected, but the rectosigmoid is spared in 60% of cases and in 10% the disease is confined to the right colon. Exposure of the human colon to C. difficile toxins is followed by shedding of cells from the basement membrane into the lumen leaving a shallow ulcer. The serum protein, mucus and inflammatory cells flow outward from the ulcer, creating the typical colonic pseudomembrane. The spewing forth of the inflammatory exudate from the mucosal ulcerations produces the typical „volcano” or „summit” lesions of C. difficile colitis.

• #2 Apoptosis of intestinal epithelial cells restricts Clostridium difficile infection in a model of pseudomembranous colitis | Nature Communications

  https://www.nature.com/articles/s41467-018-07386-5

  These findings suggest that C. difficile-induced IEC apoptosis is an early host defense mechanism that contributes to bacterial restriction and toxin production, most likely by promoting clearance of infected cells in the intestinal epithelium by professional phagocytes and infiltrating neutrophils.

• #2 Clostridioides (Clostridium) Difficile Colitis: Background, Etiology, Pathophysiology

  https://emedicine.medscape.com/article/186458-overview

  The NAP1 hypervirulent strain of C difficile is associated with the most serious sequelae of CDI, causing severe and fulminant colitis that is characterized by leukocytosis, renal failure, and toxic megacolon. […] The overall suggestion from this study is that the substance P receptor is very important in the pathogenesis of inflammatory diarrhea. […] Further insight into the genetics of C difficile toxin A reveals that the main binding protein is gp96. In addition, it has been found that C difficile has potent stimulatory activity for the Nod1 gene, and mice who were homozygous knockouts for Nod1 had increased lethality to CDI despite similar levels of intestinal damage relative to control the mice. The implication of this study is that Nod1 regulates the susceptibility to C difficile. […] Ultimately, many of the genetic influences on CDI and the clinical course of C difficile colitis likely remain unknown. At this point, it is understood that subtle differences in the immune system may significantly influence the natural history of C difficile disease.

• #2 Pseudomembranous colitis: Not always Clostridium difficile | Cleveland Clinic Journal of Medicine

  https://www.ccjm.org/content/83/5/361

  Although most often seen in C difficile infection, pseudomembranous colitis is a nonspecific pattern of injury resulting from decreased oxygenation, endothelial damage, and impaired blood flow to the mucosa that can be triggered by a number of disease states. […] When pseudomembranous colitis is confirmed endoscopically, C difficile infection naturally comes to mind, but the two terms are not interchangeable. A wide differential diagnosis should be maintained, especially when there are clues that C difficile infection may not be the correct diagnosis. […] Microvascular thrombosis is the likely mechanism in a number of non-C difficile causes of pseudomembranous colitis. […] In most patients with enterohemorrhagic E coli O157:H7 infection, histologic review of colonic mucosal biopsies has revealed fibrin and platelet thrombi in the capillaries, suggesting microvascular thrombosis.

• #2 A Case Report of Pseudomembranous Colitis Resulting from Clostridium difficile Infection Successfully Treated with Fidaxomicin | Cardoso | Journal of Medical Cases

  https://www.journalmc.org/index.php/JMC/article/view/2632/1988

  Our patient was considered to be at high risk of PMC recurrence and indeed suffered a recurrence soon after completing first-line treatment with vancomycin. […] Recently approved therapies for the treatment of CDI include fidaxomicin – the first-in-class macrocyclic antibiotic. It acts by inhibiting the RNA polymerase of C. difficile, causing cell death. Fidaxomicin has selective bactericidal activity against C. difficile, which is in contrast to vancomycin’s bacteriostatic activity against this organism. […] Therefore, fidaxomicin may be an appropriate alternative therapy in cases of recurrence, and may be appropriate even during the first episode of CDI in patient at high risk of recurrence.

• #2 Pseudomembranous Colitis: Symptoms and Treatment | Doctor

  https://patient.info/doctor/pseudomembranous-colitis

  Pseudomembranous colitis (PMC) is an acute, exudative colitis usually caused by Clostridioides difficile (C. difficile- formerly Clostridium difficile). […] PMC has emerged, particularly in recent years, as a major and very expensive healthcare problem. Spores formed by the organism are implicated in spread of infection and have implications for hygiene and prevention of infection. C. difficile is an anaerobic Gram-positive rod which secretes two types of toxin (A and B), which cause disruption to the barrier function of the colonic mucosa. They are cytotoxic to cells of the intestinal tract. Toxin B is about 1,000 times more potent than Toxin A. […] Diagnosis in CDI and PMC focuses on detection either of C. difficile or of its toxins in stool samples. The particular method used and the number of samples required will depend on the laboratory. […] Faecal microbiota transplant (FMT) aims to restore a healthy gut microbiome in people who have recurrent or refractory Clostridioides difficile infections. It involves transferring intestinal bacteria and other microorganisms from healthy donor faeces into the gut of the recipient.

• #2 Non-clostridium difficile induced pseudomembranous colitis

  https://www.wjgnet.com/2307-8960/full/v11/i5/979.htm

  Over the years, other causes of pseudomembranous colitis have been increasingly identified. […] The absence of Clostridium Difficile on testing or failure of response to Clostridium difficile treatment in a patient with pseudomembranes on colonoscopy should encourage physicians to evaluate for other causes of colitis. […] Symptoms of pseudomembranous colitis include watery diarrhea with pus or mucus in stool. This is the commonest symptom in the majority of patients, followed by abdominal pain/cramps and fever. […] Pseudomembranes are composed of mucus, fibrinous material, inflammatory cells (neutrophils), and cellular debris over the colonic mucosa with mucosal damage of varying degrees. […] Pseudomembranous colitis can occur in patients with IBD during a flare with or without superimposed causative factors such as infections, medication, and drug usage. […] Pseudomembranous colitis is a pathological finding on endoscopy and is not only due to CDI. Infectious, inflammatory, Drug, and Ischemic causes should be investigated in a patient with endoscopic findings of pseudomembranous colitis and negative CDI on testing or refractory to CDI treatment.

• #3 Pseudomembranous colitis: Not always Clostridium difficile | Cleveland Clinic Journal of Medicine

  https://www.ccjm.org/content/83/5/361

  Pseudomembranous colitis is most often due to Clostridium difficile infection, but it has a variety of other causes, including other infections, ischemia, medications, and inflammatory mucosal diseases. […] When pseudomembranes are found, one should consider these other causes if tests for C difficile are negative or if anti-C difficile therapy does not produce a response. […] Pseudomembranous colitis is a nonspecific finding that suggests a larger disease process. […] Associated signs and symptoms, including fever, abdominal pain, leukocytosis, diarrhea, toxic megacolon, and electrolyte imbalances, may portend a life-threatening condition. […] A pseudomembrane is a layer of fibropurulent exudate composed of acute inflammatory cells and mucus originating from inflamed and erupting crypts.

• #3 Pseudomembranous Colitis: What It Is, Symptoms, Causes, Treatment

  https://my.clevelandclinic.org/health/diseases/17718-pseudomembranous-colitis

  Pseudomembranous colitis (PMC) is a severe form of colitis. In this condition, something attacks and injures your colon lining (mucosa). It might be bacteria, toxins or another illness. Your colon mucosa develops thickened, scab-like plaques over the wounds. Your healthcare provider might call these pseudomembranes. […] C. difficile produces toxins that injure your colon mucosa, causing cell death. C. diff infection also can become unusually severe, unusually fast. C. diff infection usually happens after you’ve taken antibiotics. Antibiotics reduce the other bacteria in your gut, but they don’t affect C. diff. This allows C. diff to quickly grow out of control. […] Other causes of colitis can also lead to pseudomembranous colitis, including: Staphylococcus aureus infection, E. coli infection, Cytomegalovirus infection, Microscopic colitis, Behets disease, Ischemic colitis, Chemotherapy drugs, Cocaine use, Vasculitis, Heavy metal poisoning. In these cases, colitis is more severe or more complicated than usual. Complications can include reduced blood flow to your colon mucosa (ischemia), which can lead to tissue death and pseudomembranes. Preexisting conditions like inflammatory bowel disease (IBD) may also make your colon more vulnerable. […] If C. diff infection is the cause of your pseudomembranous colitis, there are a few drugs that can treat it. Your provider will choose the best one for you. Drugs to treat C. diff infection include: Metronidazole, Vancomycin, Fidaxomicin.

• #3 Basic and Clinical Aspects of Clostridium Difficile Colitis

  http://www.scielo.org.pe/scielo.php?script=sci_arttext&pid=S1022-51292004000300008

  C. difficile colitis has been shown to develop in patients taking antibiotics; however, neither the number of antibiotics nor the duration of therapy was a factor in predisposing patients to infection. […] Infection occurs via the fecal-oral route. The spores resist stomach acid and develop into a vegetative form in the colon. C. difficile toxins bind to specific receptors to stimulate fluid secretion and necrosis of the mucosa associated with an inflammatory infiltrate. […] C. difficile can colonize the bowel after a disturbance of the ecology of the intestinal flora. The oral inoculation of hamsters with small doses of C. difficile is sufficient to cause colitis after treatment with antibiotics. This fact suggests that certain organisms in the normal flora prevent colonization by C. difficile. Presumably, some components of the normal intestinal flora, such as lactobacilli and bacteroides, suppress the growth or prevent the colonization of C. difficile, and antibiotics confer a predisposition to disease by inhibiting these competing organisms.

• #3 Pseudomembranous colitis Information | Mount Sinai – New York

  https://www.mountsinai.org/health-library/diseases-conditions/pseudomembranous-colitis

  Pseudomembranous colitis refers to swelling or inflammation of the large intestine (colon) due to an overgrowth of Clostridioides difficile (C difficile) bacteria. […] The C difficile bacteria normally lives in the intestine. However, too much of these bacteria may grow when you take antibiotic medicines. The bacteria give off a strong toxin that causes inflammation and bleeding in the lining of the colon. […] Any antibiotic can cause this condition. The medicines responsible for the problem most of the time are ampicillin, clindamycin, fluoroquinolones, and cephalosporins.

• #3 Pseudomembranous Colitis: Symptoms and Treatment | Doctor

  https://patient.info/doctor/pseudomembranous-colitis

  Pseudomembranous colitis (PMC) is an acute, exudative colitis usually caused by Clostridioides difficile (C. difficile- formerly Clostridium difficile). […] PMC has emerged, particularly in recent years, as a major and very expensive healthcare problem. Spores formed by the organism are implicated in spread of infection and have implications for hygiene and prevention of infection. C. difficile is an anaerobic Gram-positive rod which secretes two types of toxin (A and B), which cause disruption to the barrier function of the colonic mucosa. They are cytotoxic to cells of the intestinal tract. Toxin B is about 1,000 times more potent than Toxin A. […] Diagnosis in CDI and PMC focuses on detection either of C. difficile or of its toxins in stool samples. The particular method used and the number of samples required will depend on the laboratory. […] Faecal microbiota transplant (FMT) aims to restore a healthy gut microbiome in people who have recurrent or refractory Clostridioides difficile infections. It involves transferring intestinal bacteria and other microorganisms from healthy donor faeces into the gut of the recipient.

• #3 Clostridioides difficile infection – Knowledge @ AMBOSS

  https://www.amboss.com/us/knowledge/clostridioides-difficile-infection/

  C. difficile possesses a range of virulence factors, the most important of which are toxins A and B. […] The C. difficile strain must be toxigenic to cause the disease. Intestinal colonization by nontoxigenic strains will result in asymptomatic carriage. […] Toxin A (enterotoxin) mechanism of action: binding to brush border of enterocytes: receptor-mediated endocytosis change of conformation exposure of active domain glycosylation of target proteins (e.g., Rac, Cdc42, RhoA) disruption of actin cytoskeleton functioning increase in epithelial permeability and apoptosis diarrhea. […] Toxin B (cytotoxin) mechanism of action: same as in toxin A, but can also cause pore formation within the endosomal membrane via insertion of the translocation domain release of endosomal content into the cytosol cytopathic effect.

• #3

  https://step1.medbullets.com/microbiology/104185/clostridioides-difficile

  causes a pseudomembranous colitis and diarrhea characterized by yellow-white plaques in intestinal mucosa […] pseudomembranous plaques are made from fibrin […] toxin A is an enterotoxin that binds to the intestinal brush border […] toxin B is a cytotoxin and depolymerizes actin, disrupting the cytoskeleton

• #3 Basic and Clinical Aspects of Clostridium Difficile Colitis

  http://www.scielo.org.pe/scielo.php?script=sci_arttext&pid=S1022-51292004000300008

  Pseudomembranous colitis (PMC) was first recognized as a clinical entity in the 1950s. The advent of broad-spectrum antibiotics in the 1960s led to a marked rise in the numbers of PMC patients. It soon became clear that C. difficile could be isolated from the stools of PMC patients. PMC is the classical and dramatic manifestation of C. difficile infection. It is now accepted that C. difficile is responsible for virtually all antibiotic-associated colitis. […] The presence of pseudomembranes at endoscopy is diagnostic, but such presence can only be detected in about 50% of cases. The left colon is most commonly affected, but the rectosigmoid is spared in 60% of cases and in 10% the disease is confined to the right colon. Exposure of the human colon to C. difficile toxins is followed by shedding of cells from the basement membrane into the lumen leaving a shallow ulcer. The serum protein, mucus and inflammatory cells flow outward from the ulcer, creating the typical colonic pseudomembrane. The spewing forth of the inflammatory exudate from the mucosal ulcerations produces the typical „volcano” or „summit” lesions of C. difficile colitis.

• #4 Exploring the Toxin-Mediated Mechanisms in Clostridioides difficile Infection

  https://www.mdpi.com/2076-2607/12/5/1004

  Recent findings indicate that TcdB is more closely associated with CDI severity, supported by clinical strains predominantly producing TcdB and strains lacking TcdA but causing severe disease. […] These toxins are pivotal in CDI pathogenesis, disrupting cell adhesion, and cytoskeletal rearrangements, and triggering pro-inflammatory responses and cell death. […] The endocytosis and release of TcdA and TcdB into the cytosol of the host cell can be distinguished into five stages: (i) binding of the toxins to cell surface receptors; (ii) cellular uptake via endocytosis; (iii) formation of pores in endosomal membrane; (iv) translocation of the toxin into the cytosol; (v) glycosylation of Rho/Ras GTPases; and (vi) cellular impacts. […] Once GTD is released into the cytosol, it selectively transfers UDP-glucose to Rho and Ras proteins, leading to their inactivation.

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