University Place Wednesday Nite at the Lab  Sleuthing, Reducing and Resolving Clostridium Difficile Infections  Nasia Safdar May 30,12 UP725 CC >> Welcome everyone to Wednesday Nite at the Lab. I'm Tom Zinnen. I work here at the UW-Madison Biotechnology Center. I also work for UW-Extension, Cooperative Extension. On behalf of those folks and our other sponsors, including Wisconsin Public Television, the Wisconsin Alumni Association and the Science Alliance, thanks for coming to Wednesday Nite at the Lab. We do this every Wednesday night, 50 times a year. Tonight it's my pleasure to be able to introduce to you Professor Nasia Safdar. She studied medicine at the Aga Khan University Medical College in Karachi, Pakistan before coming to Madison in 1997. As a resident in internal medicine here at the UW Hospital and Clinics. She earned a Master of Public Health in 2002 and took a fellowship in Women's Health from 2002 to 2005. 

In 2006 she became an assistant professor in the section of infectious diseases, the Department of Medicine here at the UW Hospital and Clinics. Since 2009 she has also served as a staff physician in infectious diseases at the William S. Middleton Memorial Veterans Hospital here in Madison. She is board certified in infectious diseases and internal medicine. Tonight she gets to talk to us about sleuthing, reducing and resolving Clostridium Difficile infections. Please join me in welcoming Dr. Safdar to Wednesday Nite at the Lab. [applause] >> Thank you, Tom. Good evening everyone. It's a great pleasure to be here. Today we'll be talking about Clostridium Difficile infections. I think it's always instructive to go back and figure out how it all began. 

The way it all began with C.Dif, which is something that, when I was a resident ten years ago, we used to see a little bit of. Only enough to say that it's a nuisance but it's something that's readily treatable and nothing that we need to worry about. To the situation that we have now, where most of our clinics are filled with people with Clostridium Difficile infection. It's an increasingly virulent infection, and increasingly difficult to treat. Things have clearly changed. It was first described in 1936, by Hall and O'Toole, and they all felt that it was a commensal organism of the GI tract. Something that was there normally and was not pathogenic and did not cause any symptoms to be of any concern. It was initially described in new-born infants. Interestingly, new-born infants, up to probably age, I would say, two years, children still, although they can harbor C.Dif, they don't get clinical disease from C.Difficile infection. That's not to say that they can't pass it on to their moms and dads, and other people they come in contact with. 

But they, themselves, do not get sick from it. The causes of that is unclear. After it was described in 1936, not much happened. A lot of other advances in science happened, but nothing related to C.Dif necessarily. Until the 1970s when the syndrome came about where people recognized that individuals who where being given an antibiotic called Clindamycin subsequently developed inflammation of the intestine. This syndrome was called Clindamycin-Associated Colitis, but it wasn't clear at all that it was infectious. Several lines of investigation then converged to define what Clindamycin-associated colitis was. It wasn't until the late '70s when John Bartlett from Johns Hopkins discovered that if you gave hamsters Clindamycin and then gave then Clostridium it produced the exact same syndrome as Clindamycin-associated colitis did. It became pretty clear that Clostridium Difficile was toxin-producing organism that, when ingested by individuals in the right setting, gave them a severe colitis, or inflammation of the intestine. It's a strictly antirobe, spore-producing organism that is very difficult to grow. 

That's how it got it's name, Clostridium Difficile. It required several antibiotic in the media to grow, and has a characteristic odor which people say is like elephant manure. If you know what that smells like, I don't know what kind of company you keep. [laughter] I mean, it's difficult. It's a barnyard odor. That's helps. Some people would be familiar with that. Here's what it looks like. The endospore. You know, over the last 20-30 years, once it was described, people recognized that you could treat it with an antibiotic called Metronidazole. 

So paradoxically, a syndrome that's caused by an antibiotic can also be treated with an antiinfective. People did find the outcomes were not terribly bad. They became sick with it, but at least they weren't dying of it. But in the last ten years there was a slew of investigations that all were published in major medical journals indicating that there is a new virulent strain of C.Difficile. This is one of probably five or six. It's not a problem that is localized just to this country, or even to this continent, but is a global issue that people are struggling to come to grips with. There was one multi-institutional outbreak of C.Difficile in this country. This is the one from Canada, but there's similar ones in this country, that was associated with high morbidity and very high mortality. It was pretty clear that super-bug back. So we had to find a way to combat it. 

Of course, the first thing you do, is you have a support group. So there is a bone fide C.Difficile support group. There is a wrist band that you can order. You do have to pay shipping, but other than that it's not expensive. Why is it that C.Dif has changed over the last few years. In order to get into that it's instructive to see what is the population that it attacks. Here you see on this slide, from 1991 all the way to the end of 2003, you'll notice the rates of C.Difficile infection which have been stratified by age. The highest rates and the most astronomical rise, enough so that the scale had to be truncated, is in people over the age of 65. Whom I used to call older people, but rapidly approaching that myself, I now call middle-aged. People over the age of 65 are at high risk. 

We'll go into why that might be. If you look at national estimates of US short-stay hospitals and their diagnoses, previously it used to be infrequent that C.Difficile would be listed as either a primary diagnosis or as any diagnosis. But in the last five, ten years are so, you see that orange line here is any diagnosis is rapidly creeping up. Some people question, is this really an increase in incidence or is this more that we are now diagnosing it better and detecting it sooner and more accurately. It's probably a combination of both. Now this trend hasn't really changed over the last several years and our diagnostic methods have been pretty good for a number of years. So we suspect that it's really a rise in incidence that is happening. The is a number of definitions that we use. There are national guidelines for how to define C.Difficile infection. It has importance because now we report C.Difficile infections to the CDC which keeps track of national rates of these infections. 

In order to attribute to an institution, and therefore risk being labeled as an institution that has C.Difficile in it, you have to make sure that you are accurately defining it. The way we usually say is, a case of CDI or C.Difficile infection, somebody has to have diarrhea or toxic megacolan which is defined as dilation of the intestine, without any other known etiology, and you have to test specifically for C.Difficile in the stool, either by means of a toxic assay or a PCR. Or PMC, which is pseudomembranous colitis, which is a specific type of colitis, has to be found on histopathilogical examination. How do we know whether it's from the community or whether it was something that was acquired inside the institution and hospitalized patients? In order to call it healthcare facility-onset the individual has to develop it more than 48 hours after they've been admitted to the hospital. The premise being that they shouldn't be incubating it at the time that they come, but they were in the hospital, then they got it, therefore it must have been acquired from somebody or something within the hospital environment. You can also have a syndrome called community-onset, but still healthcare facility- associated. This was recognized when people discovered that when hospital stays were getting shorter, individuals while they were in-house, or in the institution, felt fine, but as soon as they went home they got C.Difficile. Then they got re-admitted with that. So even though it occurred in the community, it is still clearly linked to the recent hospitalization that they had. The symptom onset is less than 30 days after last discharge from a healthcare facility, suggesting that that institution still played a role in giving the individuals C.Difficile. 

True-- Yes. >> [inaudible]  >> True community associated CDI is very rare. It's rising in incidence as well, as are most other things in the community, and spilling over into the hospital setting. But in general, most cases of C.Dif that you will see will have some connection or the other to a healthcare facility, or a recent hospitalization. 40% of people that have one episode of CDI will recur. Recurrent C.Dif is usually defined within the eight-week time-frame of the previous episode. Generally it's reported as number of CDI cases per month per 10,000 patient days. This is the rate that we follow and gets reported to the CDC, which then generates national and state-specific rates to send back to us. Now, what are the factors that people think have contributed to resurgence of C.Difficile infection? First of all, the virulence of the strain seems to be something that's new. There are these epidemic strains which weren't described before, that have now become more important. 

That's clearly one factor. C.Difficile really is a disease of resistance to antimicrobials. Most of the strains that are now prevalent are resistant to Clindamycin. Hence, when people get Clindamycin, it kills off everything else but C.Difficile over grows and thereby causes disease. There is an increasingly older immunocompromised population, which is the population at highest risk for getting C.Difficile infection. And on top of it all, is what some people think has also contributed, which is the alcohol-based handrubs which are commonly used for hand hygiene. Alcohol-based handrubs are not sporicidal and have no impact on C.Difficile. The reason there is a question mark there, is because a few studies that have been done, did not conclusively show that is you use an alcohol hand gel you are more likely to get C.Difficile. But because it doesn't work for it, I think it makes biologic plausibility and makes sense to think that, if you're using your hand washing agent as an alcohol hand gel, that C.Dif rates may rise. Those are all factors that people think have contributed. 

This is just the tip of the iceberg. The individual that you see who has clinical disease represents a fraction of everybody that is colonized or has been exposed to C.Difficile, but for one reason or another, did not get clinically sick from it. Pseudomembraneus colitis, or PMC as it's called, if you see an individual with that, 95% to 100% of the time, that's related to Clostridium Difficile. You will be able to see a positive toxin assay that will reflect that. It only accounts for about a quarter of all antibiotic- associated diarrhea. A lot of people that we give antiinfectives will get diarrhea, but when you test for C.Dif you'll find that a quarter of them with have a positive test. The remainder, we don't really know what causes it. It's thought to be a combination of perturbation of the antibiotic flora in the intestine, but nothing specific that you can specifically treat and get rid of. Hospitalized patients, about 20% of them will be exposed to C.Difficile and will carry it in their intestine for an unspecified period of time. Very few healthy adults will carry C.Difficile infection. 

Many of us, if we do, it will be nontoxigenic, or the non-toxin producing C.Difficile, which is non-pathogenic and is not of any concern. But a few of us will carry toxic Clostridium Difficile. And look at how many healthy neonates will carry C.Difficile in their intestine. More than 50%- 65% of them. What are the risk factors for CDI? Besides the age, antimicrobial exposure is something that is universally reported in people that get CDI. Some individuals after GI surgery, even independent of antiinfective use will get it. Tube feeding, as is common in ICU or hospitalized patients that are unable to eat, is a common risk factor. And in recent years this is something that surprised individuals when it came out. Proton pump inhibitors, or omeprazole or the like, that are used very widely in this country and worldwide. H2 blockers, such as Zantac or ranididine, are also risk factors for causing C.Difficile. 

Not just causing it, but also exacerbating it in people who have already gotten the infection. Yeah. >> Do they know whether the incidence of older people using those proton pump inhibitors and the H2 blockers might be the reason why the age is an issue? >> The age, I think, is an issue for a number of factors. We'll go into that in a little bit. But they did look at case controlled studies where they looked at a variety of age stratified groups, and in each age, it seemed that if you were taking a proton pump inhibitor you were at higher risk of C.Dif. Not just of C.Dif, but also of pneumonia, interestingly. Among the illnesses, and this also is something that may be relevant to age. As with age, comes other comorbidities and other illnesses. Organ transplantation and chronic kidney disease or renal failure are all factors that are associated with a high risk of CDI. Many cancer agents have activity beyond their cancer fighting potential including antibiotic properties, and so cancer chemotheropic agent independently also have a high risk of C.Difficile infection. 

So something that we keep in mind. If you were trying to get C.Difficile infection, how would go about it? The easiest way to do it is to get hospitalized for a prolonged period of time. You can see that in this slide, this is several years ago but, some things, they don't change. If you look at the length of hospital stay, at four weeks, about 50% of people will have acquired C.Difficile. Probably from the hospital environment. To avoid it, you have to make sure that your length of stay is less than a week. Not all antibiotic agents are the same. Some frequently induce C.Difficile, others infrequently induce it. So for people that have had one episode of CDI, we always take extra effort to see that if they ever need antiinfectives, for say a urinary tract infection or pneumonia, we try and chose an agent from a class that has a rare or low risk of inducing C.Difficile. But you'll notice that even agents that are used for treatment of C.Difficile have also been known to cause it. 

So in that last column on the right, under the rare induction, Medronidazole and Vancomycin are both antibiotics agents frequently used for treatment of C.Difficile and in case reports have also been shown to cause it. The ones that cause C.Difficile frequently, many of these are familiar to people in the audience here. The biggest one that is used very frequently now is quinolones, ciprofloxacin, moxifloxacin and the like. Very commonly used for pneumonia, for soft tissue infections, for urinary tract infections. Those are ones that used to be thought were infrequent inducers, but actually it's pretty clear now that they are frequent inducers. In fact, ciprofloxacin use was associated with the resurgence of the epidemic strain that's been described world-wide. The clinical spectrum, should you get exposed to C.Difficile, one of these things can happen. They don't have to be in order. You can go from having no symptoms to having toxic megacolon, or very severe illness. But generally speaking, the spectrum is that you can carry it in your intestine and nobody need be any the wiser. 

You can have antibiotic- associated diarrhea. You can have antibiotic- associated colitis with pseudomembranes, which basically means, severe colitis but not very severe colitis. Then you can have pseudmembranous colitis, which is the very severe form. Then you can fulminant colitis, which is something that requires surgery for treatment and correction. How do people acquire C.Difficile? An individual gets hospitalized and then after that, you get exposed to antimicrobials for whatever reason, either there's a urinary tract infection or pneumonia or something that requires antibiotics for treatment. Once you get antiinfectives, your normal intestine, which is perfectly capable of posing an immense amount of resistance to pathogens, no longer has quite the degree of colonization resistance, because you've killed off a lot of the good bacteria that would otherwise protect you. So the milieu is then set for invasion of a pathogen, and with C.Difficile being everywhere in the hospital environment, if you ingest that, that will set up shop in the intestine, and then one of two things will happen. You will either get sick, you will get C.Difficile colitis, or you will have asymtomatic C.Difficile colonization in your intestine, but you will not get sick. What is it that determines which of these two things will happen? It happens in a matter of days. So in less than five or six days, these events happen. 

What determines colonization verses diarrhea is very interesting to see. This was a med-analysis that looked at several perspective studies. They found that if you were colonized with C.Difficile, only one percent of people would get active disease. But if you were not colonized with C.Difficile, almost 4% of people would get active disease. There is something about successful colonization that protects you from getting clinical disease. Which is good from the viewpoint of individual patient, but from the viewpoint of spread in the hospital, it doesn't really mean much. Even if you have it in your intestine, if you're well, that's great, but you can still spread it to other people. It is the relationship between the IgG antibody against toxin A of Clostridium Difficile that determines whether one will get sick or not. We now that with aging come immunosenescence and the ability to have a deficient antibody response to pathogens. That's what most people think is why older adults are unable to mount the antibody response to fight C.Difficile. 

Renal failure and organ transplantation only compound that factor. This was a New England study published now almost 12 years ago. They looked at the incidences of both mild disease and severe disease with C.Difficile. On the X-axis you have the levels of IgG antibody against toxin A. You can see that the higher the level of IgG, the lesser the incidence of both mild disease and severe disease. If you don't have the capacity to make antibodies, you get severe disease with C.Difficile. That's led to a number of advances as far as treatment options for C.Difficile. What is the mechanism of diarrhea caused by these toxins? Well, they cause a lot of disruption of the tight junction of the cells. There's intense fluid accumulation. The cells become very permeable. 

There's intense neutriphilic infiltration with both the toxin A and the toxin B, which is the two major toxins that C.Difficile produces. Eventually the individual gets clinical disease which looks like this. This is Pseudomembranous Colitis from a colectomy specimen. The yellow things that you see are all neutriphiled and -- excavated would just go to the surface of the intestine. Not something you want to have at any time. Histropathologically speaking, this is what it looks like. It's called the volcano, or the mushroom effect, which is really this intense migration of white cells to the area of inflammation. It's not specific for C.Difficile. It can look like this in other pathogens that cause intestinal problems, but more associated with this than anything else. As if that were not enough, in recent years there's been an additional toxin, beyond toxin A and toxin B that has been described with C.Difficile. 

This is called binary toxin, and the mechanism of what it does is unclear at this point. But what happens is the regulatory genes that regulate the production of toxins A and B get deleted, and so there is no control mechanism over how much of toxin A and B is produced. What people have found is that with this new strain called the B-1 or the nap-1 strain of C.Difficile, it produces 16 fold the amount of toxin a and 23 fold of the amount of toxin B that a non-epidemic strain would produce. And colstridial toxin are among the largest known to man, so there's a greater propensity for resistance to antibiotics, such as what I mentioned, Ciprofloxacin for example. There's a higher incidence of sepsis, of leukemoid reactions, meaning a very high white count when you get infection, the need for a colectomy, and death. So what is a way to diagnose C.Difficile? There's a number of ways that one can do it. There's clinical clues. There's laboratory tests, x-ray imagining and then endoscopic procedures. Many nurses in the hospital will swear that they can tell if a patient has C.Difficile. This was the basis of a study that looked at whether an individual's sense of smell can actually predict if diarrhea is caused by C.Difficile verses something else. 

This was one study where they looked at nursing personnel where they had stools with C.Difficile, and they found that they could detect it. Sensitivity was 55%, so about half the time nursing personnel could tell if somebody had C.Dif or not. But it has led to development, or in the process of development, of an artificial nose. People think that might be the first clue to be able to tell if somebody has C.Dif. It doesn't have to be watery stool. Semi-formed stool, anything that takes the shape of the container is predicative of C.Difficile infection. But blood in the stool and stool color are not predictive of whether somebody will have C.Difficile or not. Certain antibiotics, like I said, are more likely than others. There is one thing in recent years that has panned out to be of interest, and that's the number of white count, or white cells, in the blood of the individual that's suspected C.Difficile. These people stratified white count into three different strata; 15,000 to 19,000, 20,000 to 29,000 and then more than 30,000. 

They looked at, in hospitalized people, what were the causes of that high white count. Infection was the major cause in about half the people regardless of which stratum you looked in. The rest was things like medications, like hematologic malignancy, leukemia for example, inflammations or medications. Then they focused on the infection. If it's infection that's causing the high white count, what type of infection is it? And within the infections there is a number of possibilities in hospitalized people. They found that after you've excluded lung infection, which is the most common type that's going to cause a high white count, Clostridium Difficile, urinary tract and soft tissue infections account for the majority of white count rises. This has become an interesting predictor. We get called many times to do infectious disease consult in hospitalized people who have a high white count but nothing else. Often times we find it heralds C.Difficile infection which will become apparent a couple days later but not necessarily at the time. The white count seems to be an early predictor of severe C.Difficile infection. 

If you were going to diagnose using lab testing the PCR has really supplanted all the other tests that are mentioned here. It has a very rapid turn around time, a very high sensitivity and is very specific as well. The other tests, such as Eliza's, or a culture, are much more labor intensive and don't nearly provide the degree of accuracy that one would want to see in a test like this. There are many toxin assays that are available on the market. It's important to remember that they don't all detect both toxins. Toxin A negative but toxin B positive strains been described. In fact, there was a case at the VA that was published in the Annuals of Internal Medicine several years ago where the VA had a toxin kit that only looked for toxin A and not toxin B, and the individual had toxin A negative C.Dif and died of it eventually, and in an autopsy was found to have C.Difficile. When they investigated it further, they found that that strain would not have been detected by the test that they were doing. The toxin B has a rounding effect on the cells. This is a fiber glass so you can see, on the left they're rounded, on the right they're a spindle shape like they should be. 

There's a lot of infection control implications for Clostridium Difficile. There is heavy environmental contamination. This would surprise people now, but it wasn't always the case that healthcare workers would wear gloves when they were dealing with stool. I mean, it seems incredible. But this is from the 1970s, where this poster was put up on the wards, where they said you wear gloves when you're dealing with body fluids and excrement so to speak. What are the things for infection control that will reduce C.Difficile? There's some things that have been proven, some that are highly probable, and some that have yet been not tested enough. Restriction of antiinfectives is clear, that that reduces C.Difficile. Glove use by healthcare workers has also been shown. Hand washing between patients as well. We keep patients in contact precautions or isolation precautions, meaning that they have an individual room, and all healthcare workers that go in will wash their hands and will wear gowns and gloves when taking care of the individual with C.Difficile. 

It's very likely that that interrupts transmission, but it hasn't been conclusively shown at this point. That's why it's probably over there. Treatment of people who are asymptomatic carriers has not been shown to work. Even though you can eradicate it briefly, you almost always reacquire it. Isolation of people who are just asymptomatic, don't have symptoms but are carriers of C.Difficile, has really been untested at this point. The reason isolation is of interest is because, it's not a simple thing first of all, to keep somebody in contact precautions mainly because some studies have shown that there are adverse effects associated with keeping people in contact precautions. There is some psychological issues in individuals who may feel isolated. And it's also been shown that healthcare workers are less likely to enter the rooms of patients in contact precautions. Now whether entering it less likely translates into worse care is not known, but very likely. If you don't see the patient and you're just waving at them from the door, you're not likely to learn much. 

Care from the door has definitely been a problem with contact precautions. If you were going to treat C.Difficile, the biggest thing that we sometimes forget is that you have to discontinue the trigger. Which can sometimes be done, but most of the time, when I see people in clinic, they're on antibiotics for a reason, then they get C.Difficile, and they still need those other antiinfectives. It's difficult to completely discontinue them. At the very least, one should make an effort to transfer it to a different class that is less likely to exacerbate C.Difficile. Several randomized trials now, comparing the two main antibiotics. One is Vancomycin and one is Metronidazole. Both have equivalent treatment success, between 88%-90%, a similar relapse rates, both are given four times a day. Vanocmycin is FDA approved. Metronidazole is not, so it's off-label use. 

Vancomycin costs thousands of dollars. Metronidazole is very cheap. Vancomycin has hardly any side effects. Metronidazole can cause neurotoxicity in people, with numbness and tingling of their arms and legs, which is often irreversible if it's continued. So they both have their pros and cons, but like I said, initially when the disease was mild, you gave people Metronidazole for a couple of weeks, things resolved. Now that we're seeing people with prolonged disease, with many recurrences, if you have them on Metronidazole for a month of so, they will all get neurological damage and that's obviously not something that's desirable. Should we use Metronidazole for a Clostridium associated infection? Several years ago in Clinical Infectious Diseases there was an interesting editorial. What it said was that if somebody has C.Difficile it's perfectly fine to prescribe Metronidazole for your mother-in-law, but it's not something that you would ever give to your mother. [laughter] The reason is this, when they looked at the outbreaks of C.Difficile they found that people had almost a 50% reoccurrence rate when they were given Metronidazole compared with Vancomycin. Now, it's unclear why, but many people feel it's because Metronidazole is absorbed from the GI tract, gets into the blood, and therefore doesn't hang around long enough in the intestine to actually work very well. 

Whereas Vancomycin has no absorption and stays in the intestine, and therefore does a better job. I think the answer to that question is still unclear. The recommendations now say that is somebody has anything more than mild disease, you might prefer Vancomycin to Metronidazole. If it's really mild disease it's okay to do Metronidazole as the first one. We strongly recommend that people do not take antimotility agents, like Lomotil. It's very tempting, because it's profuse diarrhea, and people have things to do and places to go. But what it does is it keeps the toxin in the intestine and thereby exacerbate symptoms and makes things worse. We generally tell people not to use anything that will allow their gut to slow down until the toxin has been expelled and symptoms have been resolved. This study supported that. Lincomycin was the older name for Clindamycin, so that same syndrome of Clindamycin- associated colitis, when they randomized people to either getting an antimotility agent or not, they found that outcomes where worse when they were using antimotility agents. 

This is a question that I get asked all the time, because our lab works on probiotics for reducing Clostridium Difficile infection. So people ask, healthy bacteria, if they replenish the intestine, can they work against C.Difficile? It's pretty clear that they work against antibiotic-associated diarrhea. Which is why, when anyone gets antiinfective for any reason, they should always take a probiatic with it. Then generally take it for two weeks after the antibiotics have stopped so that the gut can repopulate. It's not clear which probiotic one should use. You'll notice this metanalysis this heterogeneity was pretty high. Even though the relative risk was almost 50% lower than people that were taking probiotics. The studies were so different, and the types of probiotics they used, how long they gave it, the population they used it in, that it is impossible to recommend one over the other. They all seem to fairly similar with the exception of this one, which is Saccharomyces Boulardii. This is the one that was subjected to a very rigorous randomized double blind trial. 

It was placebo controlled. They had people with Clostridium Difficile-associated diarrhea, and they gave them a standard of care, with was Metronidazole, so some antibiotic to treat C.Difficile, and they gave them either the probiotic in addition or they gave them placebo. What you found was, that if you look at the initial episode, which is the orange and the purple there, that there was no real difference between failure rates whether people were given probiotic or placebo. But when you look at recurrence, which is the red and the green lines here, there you can see that people on just placebo had a much higher failure rate than people who were given Saccharomyces Boulardii. Based on this, FDA approval was pursued but eventually was not granted, mainly because of concerns that this is a yeast, and if you give yeast to immunocompromised people you can get yeast in the bloodstream and that can cause problems as well. Having said that, because it's a probiotic, it doesn't come under the same regulations as drugs or medications does. So, even though it didn't get FDA approval as a drug, it's freely available and you can go to any store, Walgreen's, for example, and buy it for use for C.Difficile. More recently, lactobacillus-based preparations have been found to be helpful. This probiotic was given to individuals who were at risk for C.Difficile twice a day. This is DanActive here and Actamil in Europe. 

This was published in the British Medical Journal. The primary outcome for this group was diarrhea. They looked at C.Difficile as a secondary outcome. But what they found was, in the lower half of that slide, people that were given probiotic, there were no cases of C.Difficile. People that were not given probiotic, they had a 17% incidence in the control group of C.Difficile, which reached statistical significance. Based on that, it would seem that probiotics may have a role to play for prevention of C.Difficile. They don't seem to have a role, at least known at this point, of adjunctive treatment for C.Difficile. Once it's already acquired, I think it's too late at that point, but for prevention it seems to have value. The study has been criticized because it wasn't very generalizable. Out of the thousands of people that they scene, only a few hundred met criteria. 

They had a very careful selection group that most of us in this room wouldn't qualify for. I think that's why more studies are needed, but it seems to have promise. I think it should be looked at further. The thing you want to avoid with C.Difficile is fulminant colitis, which is this. Here is the bowel here. The black areas are all gas in the intestine. Normally it's pretty narrow, and it looks like a bowel. This is very dilated, toxic megacolon. The only treatment for that is surgery. It's not of any value to start people on Vancomycin at that time. 

In fact, the more you delay, the more likely they are to not do well with it. Early surgical consideration in ICU patients is really critical. So, well, what do we do then? We have limited options for treatment. We know that not many of them work very well. People are getting recurring disease. So what about doing a fecal transplant or-- Now, give it a moment. [laughter] I think people this reflex reaction. I agree, it's not aesthetically very pleasing, but this study and many since, have looked at, if you do rectal infusion of normal feces. The question came up, what's normal feces? Who should you get this from? And of course it's always a spouse, isn't it, that has to volunteer for things like that. Usually, yes, it should be a family member who generally share your same flora. 

People suggested medical students, but I think that came under the heading of coercion and that didn't go over very far. This, you'll notice, is from-- Does it have the date here? No, it doesn't. This is from several years ago. There was no interest to this until recently, but now that we're stuck in the situation where we have very limited options, there is a trial that's ongoing on fecal transplant. There are a lot of institutions that are doing it. It seems to have promise because it does have very good efficacy. It's just a matter of, you don't want to introduce other pathogens to the individual that you're giving the stool to. There has to be a fairly rigorous protocol that's followed. But in last year's infectious diseases meetings, there were several abstracts on the utility of fecal transplant for C.Difficile, as well as many jokes. You know, no production shortage. 

Very little addiction potential. There's really no end to what people will say about this. [laughter] What we've learned about C.Difficile then has meant that new treatments are on the horizon. So what I was mentioning earlier about the IgG antibody. If that's low you get severe disease. Naturally, the next step then was to develop a monoclonal antibody and give it to people and see if that reduced the risk of recurrence. That's one thing that's on the horizon that's not clinically available yet. The newest drug on the market is Fidaxomicin, which has reduced recurrences when compared with Vancomycin, but it also costs about $28,000 for 10 day course. It's not really affordable for many people that need it. Rifaximin is another antibiotic that is available. 

Tolevamer is a polymer that physically binds the toxin in the intestine and is not yet available but is in studies to look at. This New England Journal publication looked at treatment with monoclonal antibodies. Again C.Difficile toxin. This was a infusion that they gave people, and what they found was, that in the placebo group, recurrence rate was about 25% and the antibody group was about 7%. That's a substantial decline in the recurrence rate, because that's when people get sicker and sicker. They deal with one and they get another recurrence. Of course, the cycle continues. This is promising. It's in phase three trials. But is not available. 

We don't really know how much the cost will be, but I imagine it's not going to be slight when it does come out. If you use Rifampin-based antibiotics for treatment of C.Difficile, very quickly, it will become resistant to Rifampin. That happens with many of the other antibiotics that we've used for C.Difficile. Surprisingly, there hasn't been a lot of Vancomycin resistance in C.Difficile thus far. So most of the failures that occur are, in general, said to be failures on the part of the host, you know, if their immune system is compromised then the antibiotic doesn't do much. This was the publication on Fidaxomicin verses Vancomycin. Here is what that showed. If you look at clinical cure on the left, this is per protocol and modified intention to treat, which is just two different ways of comparing Fidaxomicin and Vancomycin. So for clinical cure, they were fairly similar, but look at the differences in recurrence, which is the middle column there. Fidaxomicin had a much lower rate of recurrence than Vancomycin did. 

That's what led to the FDA approval, and that's why it seems very attractive, but we do restrict it because it's one of the last things we have for C.Difficile, and in the outpatient setting, it's very expensive. Here is a testament to the tenacity of C.Difficile. Remember that earlier slide I had that talked about Clindamycin-associated colitis? Well, that was a child, a 13-year-old child, that they took a stool specimen from and sent to the CDC to try and figure out what the cause of Clindamycin-associated colitis was at the time. The specimen was lost and, you know, there was a lot of angst and so on, but nobody could find it and that was that. Then 21 years later they went into the archives, they recovered to isolate, it was still viable and it was still producing toxin, despite having been stored in probably sub-optimal conditions. So people have enterprising ways, you know, of doing things. Recently there has been populations that hitherto believed to be a low-risk that are now getting C.Difficile. The primary population here is peri-partium women which felt that if they get antibiotics because they're carrying, say, group B strep in vaginal or rectal area, they'll get penicillin or they'll get Clindamycin to protect the child. Then they'll get Clindamycin. Or the neonate who will be colonized with C.Difficile, will give it to the mom, who will then get severe C.Difficile. 

And probably a delay in diagnosis there, because you don't really think of, you know-- Here's the first case. This is a 31-year-old woman who was 14 week pregnant with twins and then got C.Difficile. That's not a population that you would really think would be high risk. But I think it's a reflection of how severe the disease has become and how virulent the strains are. That it's affecting people that normally should be able to protect themselves. Finally, this is a situation where a dog may not always be your best friend. This was an epidemic C.Difficile strain in a hospital visitation dog. Many healthcare institutions have hospital visitation dog programs and policies, and they're clearly of great value in people who are rehabbing from strokes or other neurologic syndromes. But it seems to be very possible that sometimes you can get infections from them as well. If not C.Difficile, but others as well. 

Just something to keep in mind. I think that's all I have. I'm happy to take questions, and thank you for your attention. [applause]