C. Difficile Infection (Antibiotics)

00:00 Now let's talk about the antibiotics that we need to worry about. The ones that seem to be frequently linked to antibiotic-associated colitis are ampicillin and amoxicillin, the cephalosporins, the clindamycin and particularly the fluoroquinolones and these organisms are fairly broad spectrum. Less frequently, we talk about the tetracyclines, sulfonamides, erythromycin. We don't use much chloramphenicol in the United States anymore and trimethoprim and I'll start out by saying that I have never recognized antibiotic colitis due to an aminoglycoside. The aminoglycosides like gentamicin essentially only hit aerobic gram-negative rods for all practical purposes and it must be as rare as hen’s teeth for metronidazole to cause antibiotic colitis because metronidazole and vancomycin are two of the treatments we use to kill <i>Clostridium difficile</i>.

01:18 So I've never seen it but it's on the list as a rare cause. Now this organism, <i>Clostridium difficile</i>, like other <i>Clostridia</i> is a spore-forming organism. So when it falls upon hard times even in the intestine, it may form spores which allow it to survive under environmental circumstances that are unfavorable to the organism and it's these spores that can be ingested and also can disseminate and that dissemination sometimes takes place even in the hospital and they can colonize the surface when antibiotics have altered their colonization resistance. So let's say somebody is receiving an antibiotic that even works against <i>Clostridium difficile</i> or the organism may form spores and the spores are essentially impervious even to antibiotics that kill <i>Clostridium difficile</i>. So in the hospital, if someone has antibiotic colitis caused by this bacterium, we need to isolate the patient so barrier precautions are needed. So this organism makes essentially 3 toxins. It makes an A toxin, TcdA, which would be Toxin of <i>Clostridium difficile</i> A.

02:52 TcdB and it's really the B toxin that's the bad boy, it's a thousand times more potent than the A toxin and then it makes a binary toxin that is very mild in terms of its effect on the GI mucosa.

03:14 So what the toxin does is it glycosylates and inactivates GTPases and GTPases are enzymes which control actin cytoskeleton of cells. If you disrupt the actin cytoskeleton, you're going to kill the cell. You also, in killing the cells, disrupt the barrier function of the mucosa and the cells either directly are killed or they become apoptotic and it's no surprise that you get an inflammatory response with an infection caused by <i>Clostridium difficile</i>. So the toxins enter the cytoplasm. They then glycosylate the RhoB protein, which is the regulator of the actin cytoskeleton. They disrupt the actin cytoskeleton and kill the cell. So let's talk about the spectrum of disease. The expression of the disease how severe it is depends upon the host's susceptibility or the immunity. Some strains are more virulent than others and the timing and the type of antibiotic therapy, for instance if you started somebody on ampicillin and they received a short course, well <i>Clostridium difficile</i> may try to overgrow but after stopping the antibiotic, the other organisms come back quickly and the diarrhea resolves spontaneously. It was due to <i>Clostridium difficile</i> but it was self-limited. So, the other thing is that antibiotic-associated diarrhea may have other causes. You can also carry <i>Clostridium difficile</i> as I like to say the students down there in the dark asymptomatically. I would guess a sizable minority of us have this organism, maybe 30% of us have this organism in our intestine now. Then there's the diarrhea that starts the <i>C. difficile</i> associated diarrhea and if it's progressive it will become pseudomembranous colitis and it can result in fulminant colitis with toxic megacolon and death.

05:59 So how do you diagnose antibiotic-associated colitis. Well, you have to demonstrate that the toxins are in the stool. We do that commonly using an enzyme immunoassay and we ordinarily submit 2 specimens and if you do that the sensitivity is greater than 90% so we can easily diagnose this. Now, if the diagnosis remains in doubt or let's say we know the patient has it but they are no better, it may be time to do a lower GI endoscopy and that's where we see this pseudomembranous colitis. Now, they call it pseudomembranous colitis, it's a very adherent not pseudomembrane, not a real membrane, composed of white cells and the sloughed mucosal epithelium. That's what you're looking at. So, how do you then manage antibiotic-associated colitis? Well, if the initial episode is mild or moderate, then the white count in the blood maybe less than 15,000, they have normal renal function, the treatment is metronidazole. On the other hand if the initial episode is severe and they got an elevated white count, they've got an elevated creatinine, and they are quite sick, you go ahead and start oral, not IV, but oral vancomycin. Now vancomycin is a cell wall agent active against gram-positive organisms and this is a gram-positive rod and the benefit of vancomycin is it only gets gram-positive organisms so it's not going to affect any of the others in the intestine, they are not gram positive, and it's not absorbed so it's not going to cause any systemic toxicity. It's a benign drug when you take it orally, it's got it's problems when you give it IV. So vancomycin is pretty effective therapy for even a severe initial episode. So let's say that it's a severe episode as not only severe but it's complicated by hypotension, shock, ileus or megacolon. Now we've really got a problem on our hands and so now we use vancomycin plus metronidazole and if the patient's intestines have stopped working if they have an ileus, we may have to give vancomycin by rectal enema. So, one of the problems with <i>C. diff</i> infections is sometimes they relapse and if this is their first relapse we would treat them the same as if the initial episode.

09:00 If it's the second recurrence, we've got to do tricks with the vancomycin and this is why we do the tricks, we kind of taper and/or pause the vancomycin. So let's say a patient has <i>C. diff</i> in their intestine and we're trying to kill it. Okay you start vancomycin, now some of those <i>C. diff</i> will turn from the vegetative form into the spores. Well, they're not going to be susceptible, the vancomycin. So after you stop the vancomycin, those spores germinate, back they come and back comes another episode. So you can fool the organism by giving vancomycin for a time waiting until the spores germinate and hit them again, wait, and then hit them again. That's the idea behind post therapy. What's really promising in the treatment of particularly severe or recurrent <i>C. difficile</i> infection is giving, I know it sounds terrible, a fecal transplant from people who donate normal stool and the idea is that normal stool contains other bacteria that once they get into the colon will quiet down the growth of <i>C. diff</i> and initially the way to give it was not very satisfactory, we give it through a colonoscope by retention enema or actually put feces down a nasogastric tube or there are now some oral capsulized frozen fecal samples that we can give like a pill and believe it or not as strange as this might sound, they are highly effective in preventing multiple recurrences, 91% efficacy.

11:15 So I think the trend now is to figure out a way to do this more aesthetically pleasing and the things that are uncertain are what actually organisms in feces do the protection? We don't know that and there are some experimental things by Seres Health: Ser-109. It's a combination of bacterial spores in pill form and it's not ready for primetime but it's promising for a recurrent <i>C. diff</i> infections. So that's a lot about <i>Clostridium difficile</i> but it needed a lot of discussion because of the importance of this in modern medicine.