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Pseudomembranous Colitis


Today we’re going to be talking about pseudomembranous colitis. So here are the learning objectives for our talk. And here’s an outline of the areas which I’d like to cover. So a brief history of Pseudomembranous Colitis, or PMC. In 1893, there was a case report from Johns Hopkins of a young lady that developed a severe diarrhea after surgery. And she died from what the authors termed “diphtheritic colitis.” And just under a century later, the causal agent was identified as Clostridium difficile from a similar case. And the way that it was identified is that stool from patients who were suffering from this disease was transferred into hamsters. And they developed a colitis. And the bacterium was deduced to be a clostridium based on neutralization of the toxin by a clostridial antitoxin. So the causal agent of pseudomembranous colitis is Clostridium difficile, which is an anaerobic, spore-forming, Gram-positive rod. It’s normally a very small component of the GI flora. And as is typical of spore-forming bacteria, it can survive on surfaces for many years. The colonization of the intestine is quite unusual in healthy people. But it’s very common in hospitalized patients. And the reason is that when you have a normal gut flora, the clostridia will not be able to multiply because they’ll be in strong competition with other bacteria which are better suited to rapid division in the colon. And what I’ve shown here is a Gram stain on the left where you can see the rods, Gram-positive rods of clostridia. And on the right-hand side, you’re seeing a false-color electron micrograph of the individual bacteria. So the pathogenesis of Clostridium difficile is the result of two proteins, ToxA and ToxB, which are produced by certain pathogenic strains of C. diff. And these proteins are produced in large quantities when you have disruption of the normal gut flora and expansion of the C. diff population. So these proteins are able to disrupt the tight junctions between intestinal epithelial cells, which you’re seeing in the center of the figure. And after you’ve got disruption, the cells will be producing a series of inflammatory mediators. And you’ll have recruitment of inflammatory cells to the site. And you’ll have disruption of the intestinal epithelium. And the recruitment of the inflammatory cells is what gives you the very characteristic pseudomembranes in Clostridium difficile infection. So for the epidemiology of C. diff, you’re more likely to come down with this pseudomembranous colitis if you previously didn’t have C. diff infection and you get exposed during hospitalization. We now know that Clostridium difficile infection and pseudomembranous colitis is associated with a recent history of antibiotic use. So those antibiotics will eliminate the normal majority population of intestinal bacteria and enable the clostridium that remain to populate the gut. So we know that patients over 65 years old are at greater risk of PMC than younger patients. And what I’ve shown here is a study from 2008 which just shows an increase in the incidence of C. diff infection and PMC in Singapore over the period from 2001 to 2006. And you can see that it’s increased quite dramatically. And it essentially tracks worldwide trends, which show that there’s an increase in C. diff infection as we’ve increased our use of antibiotics in hospitals. So the clinical presentation of PMC is quite classical. It’s usually associated with a recent antibiotic use. And I’ve listed the typical culprits that are responsible for clearing the normal gut flora and enabling C. diff to proliferate. The signs and symptoms typically develop around a week after starting antibiotics. And these patients present with diarrhea, raised total whites, abdominal pain. In severe cases, you can have toxic megacolon and intestinal perforations. So after you’ve made a tentative diagnosis of PMC, it can be confirmed by demonstrating the presence of Clostridium difficile in the stool, specifically the toxins of the C. diff. And so nowadays, that’s probably the most common form of confirmation for C. diff infection. And we use an ELISA-based method for detection of the two toxins, A and B. And you can see there, they have very high specificities, the ELISA methods. And if you are performing the stool ELISA, because the toxins are proteins, they are labile. And as such, if you cannot do the assay right away, then the stool needs to be kept cold. Another recent option is the amplification of the toxin genes. So you can collect a sample and use PCR to amplify the DNA from the bacteria that encodes the toxins. That would also give you a diagnosis of PMC. So what you’re seeing here are the famous pseudomembranes of pseudomembranous colitis. And you can see, I’ve shown two colonoscope images. And you can see that these yellowish or pale-colored pseudomembranes are present in these two patients. They’re not present in all patients. About a fifth of patients that have a mild PMC will display these pseudomembranes. The reason is these patients have the infection, but the amount of infection is not sufficient to be producing these grossly visible pseudomembranes. But certainly, in patients with more florid infection, we expect to see the pseudomembranes. Usually, for most patients, it’s sufficient to just use a shorter or the flexible sigmoidoscope to visualize the pseudomembranes. So there is an international set of guidelines to determine the severity of PMC. So it can be categorized as mild to moderate, severe, or complicated and severe. And that is based on the white cell counts and the serum creatinine. And in the severe and complicated, it’s based on the presence of shock, toxic megacolon, and intestinal ileus. So for the patient who has pseudomembranous colitis, we’ve typically arrived at the situation because they’ve been treated with antibiotics. And so ironically, to cure them of PMC, we need to give them more antibiotics. So now the standard therapy for PMC is that we try to avoid antibiotics, if possible, by stopping the current therapy. And you’ll see that a small fraction of cases will resolve without other intervention. For more mild to moderate disease, we can use oral metronidazole, or Flagyl. And if the patient has developed severe PMC, then we can go to oral vancomycin. Also, patients who have inflammatory bowel disease or patients that don’t respond to the oral metro, we can use oral vancomycin. And if the patient has been treated with metronidazole or vancomycin, there is a problem. And that is you’ll have disease recurrence in at least a quarter of these patients. And that’s why I’ve shown this slide, which is some recent research, which is quite exciting in this area. Some recent work showed that you can cure a very, very large proportion of patients with PMC by using a fecal infusion. And so what was done here is that healthy donors would supply some of their healthy donor feces. And within that feces, are the normal gut flora. And that was passaged into the duodenum via a tube. So there was no taste element involved, fortunately. And those flora were able to repopulate the intestines of patients suffering from C. diff infection. And it was found that that method of treatment was far superior to even vancomycin treatment. You can see there that there was a very high cure rate compared to vancomycin, almost an 80%, 90%, 100% cure rate, compared with only about 20% to 30% cure rate with vancomycin. So in summary, we can see that pseudomembranous colitis is essentially an overgrowth of Clostridium difficile in the colon. And these patients present with diarrhea, abdominal pain, fever, and typically a raised total white cell count. Typically occurs shortly after receiving antibiotics, about 5 to 10 days after treatment. And we can diagnose based on the presence of ToxA and ToxB toxins in the stool, also by a sigmoidoscopy to look for the presence of pseudomembranes. And we now have the treatment options of either metronidazole or vancomycin and this more recent treatment option of fecal infusion. So thank you for your time.

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