Feces Fight-Off Deadly Infection
Sudhir Dutta, M.D., Director of Gastroenterology at Sinai Hospital and Professor of Medicine at the University of Maryland School of Medicine, talks about a serious infection and how fecal transplants could be used to help the patients suffering from it.
What is C.Diff?
Dr. Dutta: C. difficile infection has been known to us for 35 years. It was first described by Dr. John Bartlett who was at Hopkins as Chief of Infectious Disease in 1978. It was known as pseudomembranous colitis in those days and we did not know what was causing it. We knew it was associated with antibiotics and it was also called an antibiotic-associated colitis, but we did not know what was the underlying cause of it. Essentially, how did it happen? It was unraveled in the subsequent 5 years and it became clear that the underlying pathogen or the causative agent was Clostridium difficile, an anaerobe that usually is in the colon of most human beings. We have lots of anaerobes in the colon and it is there most of the time, but when you take antibiotics and the good bacteria die then C. diff becomes pathogenic; it takes over and begins to cause colitis. When that was discovered it became obvious that we have to get rid of this organism and metronidazole, or Flagyl, was the antibiotic that was used to control the infection. For many years that worked very well. Metronidazole has been around for a long time and it is a cheaper medication, but we found out after 10 years or so that the organism is getting resistant to this particular antibiotic. Then came vancomycin which has become the pivotal drug, another antibiotic, for the treatment of this disease and has been helping for a long time until I think the beginning of this century when we found that there are some strains, NAP-1 strain for example, of C. diff that are even resistant to vancomycin. In fact, they are resistant to all kinds of treatments and at that point in time people started thinking of other alternative methods of treating C. diff. It has always been that some patients just did not respond to C. diff traditional treatment; 99% of the time it was okay, but in some patients it went away and came back. So, either it did not respond to the treatment or it came right back. It was called recurrent C. diff colitis and these patients were the main reason that we were looking for alternative treatments, because the way it was going these people were taking antibiotics and then the moment they stopped it, after a month, the infection came back again. In some of these people, they got so sick with this kind of treatment that they had their colons taken out. Ten years ago in our institution there were a few colons removed because the colitis was so severe that if that was not done the patients were going to die.
There are lots of deaths from C. difficile?
Dr. Dutta: C. difficile is associated with some morbidity and mortality simply because if it occurs in older people who have multiple other medical problems, it causes severe dehydration and sepsis and that causes death as a result of that.
So if the patient would not respond to the antibiotics that were out there, did they have other options?
Dr. Dutta: Well, I don’t think there were many options left because there is a new antibiotic that has come on the market which is fidaxomicin, or Dificid, but it is very expensive. It is bactericidal, so in other words it destroys these bacteria. In other words, they don’t kill the bacteria, they just control the bacteria. In this field however, the patient that has been getting fecal transplantation are those that have failed even on this new antibiotic, which is Dificid or fidaxomicin.
Can you tell me about the fecal transplant?
Dr. Dutta: For the fecal transplant the first patient came because he was referred interestingly by the discoverer, Dr. John Bartlett from Hopkins. He had this patient who had recurrent attacks of C. diff colitis and he had heard about fecal transplantation which was being done in New York by Dr. Brandt who was our visiting professor last year. Dr. Brandt has been giving the fecal transplantations by just asking them to go home and prepare something at home from the stool sample and take an enema. That was the state of art that he was doing, and this woman tried to go to New York and get an appointment with Dr. Brandt but the cost was very high for her to stay in New York and get it done. So, she talked to Dr. Bartlett who then called me and said would you consider doing it? First I said because of the nature of this disease to begin with and secondly the treatment is so unusual that I will have to go to institutional review board and I would have to review the entire literature which is going to be a lot of work. So I told the patient that to be honest, I am so busy I cannot take it upon myself at this point in time. She sat in my office and said to me that "If you don’t do it, who else will do it?" That was sort of a moment of enlightenment for me and I just looked into myself and I said, she is telling the truth. So, I told her that I would work on it. I looked into it, reviewed the literature, tried to figure out how can we do it in our environment, got the institution’s review boards of Sinai to approve it, got the microbiology lab to prepare the samples, and discussed it with people elsewhere in Minnesota. There was a group that was doing it and everybody gave some little pieces of information which was very helpful, but it was not the complete answer. For example, in Minnesota they were putting the stool sample through the NG tube into the stomach and that was not acceptable to the institution review board here at Sinai Hospital. They said "no, you can’t do that in the stomach." So we came up with the idea that we have got to make it look a little bit more defined, more scientific, so we sat down with the microbiology lab and created a program where the patients come to us, but we have to first identify donors with healthy stool samples. The donors have to be screened for all kinds of infection. Their stool has to be tested, their blood has to be tested for any of the viruses or hepatitis or any parasitic infestations, and once they have cleared that then the donor has to provide the healthy stool sample and bring it to our lab within 4 hours. The lab then has to process it with a protocol that we set up; right now it is some information that we got from Minnesota and some from New York and we created our own protocol at Sinai Hospital. The only new thing we did was everywhere else in the country they would put it either in the rectum, the fecal processed material, or they would put it in the cecum. I thought of it and I said why don’t we put it from above as well, but not in the stomach; we go further down into the small intestine and infuse the bacteria up in the jejunum. The idea was that in the colon when you put the stuff in, the colon pretty much expels it very quickly. So the bacteria may not have enough time to stay in contact with the colon and what we wanted to do was to give these bacteria more time to be in contact with the bowel. So I started from both ends, basically putting this fecal filtrate from a healthy donor into the jejunum or small intestine from above and also from below. We have done it now in 28 patients without anybody failing. Everybody has recovered and done very well.
It is a one-time treatment?
Dr. Dutta: A one-time treatment, yes.
You touched on this a little bit, but what is it actually doing? How is it interacting with the infection?
Dr. Dutta: That is a good question. What you do is you have a fecal filtrate that you infuse into the bowel, and then that fecal filtrate is nothing but zillions of bacteria that you are putting in. Some of them are known, some of them are unknown. The new DNA technology is telling us that we only know about 150 different bacteria that we have been able to culture. There are about 1500 different types of DNA-based different organisms. These different organisms are not cultured; we cannot grow them in the lab, but they are there based on DNA and they presumably do something that we don’t know. They protect the bowel probably in some way, and maybe these bacteria get killed by the antibiotic. We don’t know that, this is all speculated. So, when we infuse these fecal filtrates, we are actually putting a lot of stuff in the bowel of the recipient, in this case a patient with C. diff colitis. How they interact we don’t know. The little bit of analysis that we have received in this area suggests that the bacteria of the patient with colitis change over to the bacteria of the donor. That I think is what is happening and it sounds simple, but it is a complicated technique to establish it. We are collaborating with the Human Genomic Institute at University of Maryland and we have data on some patients where we have done the genomic analysis and we have come to accept the same kind of finding which is that the bacteria in C. diff colitis is very different. For these patients who are suffering from it, there is a dramatic change and there are some bad bacteria in there, proto-bacteria, which we did not even know before. Then once they have received the infusion of the fecal filtrate, the bacteria of this patient change completely and they get the normal ones. Now, that is happening at the molecular level. If you talk to the patients, they do not know any of this; they all know that something was done, a test was done, and they go home. To me the marvelous thing was that they feel superbly well within a day to 3 days. The longest we have had is 1 patient who is 85 years old, and she took about a week to get well. Most of them within 3 days feel perfectly fine. The bowel movements are back to normal, they don’t have cramps, they don’t have abdominal pain, and to my surprise they say they have never felt this good.
They don’t go on antibiotics again?
Dr. Dutta: No more antibiotics. They actually stop their antibiotic 5 days before our transplantation process.
Could this be used potentially for other infections or right now just for C. difficile?
Dr. Dutta: Right now just for C. diff, but it is being looked into and being done in Amsterdam and Australia and other parts of the world. We are trying to treat irritable bowel syndrome patients, inflammatory bowel disease, ulcerative colitis patients, and someday maybe Crohn’s disease patients will be treated with this kind of bacteria therapy or microbacterial therapy. Right now, I think it is very rudimentary; it is the early stages of the development of this therapy. It is going to get refined in the next 10 years and I think we will become more specific, more targeted towards a specific disorder. At that time we will be doing much better than what we do today, I think.
We are talking to your patient Ellen tomorrow, and she tells me that you saved her life. Just as a physician, how does that make you feel to be able to learn something and use it and actually help your patient?
Dr. Dutta: That is the biggest reward of what I do. My son, who is becoming a physician also, we spend long hours as physicians and everybody says, "why are you working so hard?" The reward is a happy smile on a patient’s face or their gratefulness that they express in different ways. For me personally, the 2-year-old kid that I talked about a few months ago who was referred from Hopkins again and became well, was just a delight to watch. This little kid who was all dehydrated and tired and exhausted was after 2 days was just running around like a normal child.
That is amazing.
Dr. Dutta: It is amazing. What it can potentially do, this therapy, I think needs to be explored in a very controlled and systematic manner. There are a lot of people that I get calls from who want to set it up. I have tried to give it a little bit more scientific twist rather than just telling patients, "okay, take the crap, blenderize it in a coffee thing, and just push it in." Instead of doing that, we have tried to make it a little bit more scientific in a more measured way and I hope that in doing so, we might make it more acceptable and also perhaps learn more about the process and make it more applicable to other diseases. We have just done 2 cases of ulcerative colitis now and again to our surprise they are doing marvelously well. How it works I think is going to be unraveled in the next 5 years at a molecular level. What bacteria are particularly important or critical in this improvement will be identified in due course and once we know that, then those are the bacteria that will be given in form of a capsule or a tablet to the patient. Then we will not have to deal with this stool business one day in the immediate future. That is my hope.
How do you get the donors? Is it always family or how do you choose?
Dr. Dutta: Yes. The issue of donors is very critical and we started out with the family members because we thought that would be the most acceptable, to be spouses or children or parents. That has worked very well. Now, some centers have said that the diseases run in the families and so we should not use the stool samples from the same family. When we went at it and did it, it has worked 100%, so I don’t think that argument holds much water. The donors have to be very carefully screened and the new thing in this area is the suggestion from the University of Minnesota group about a stool bank, which is dedicated for such patients who may need it at a given point in time, who are sick in the hospital. If you had in a stool bank, the samples that have been processed and stored at minus 70 degrees, then you can thaw them and give them to the patient. That is the quick way to handle the disease process. Right now I do not have that stool bank but we are in the process of setting one up. The advantage of that will be because it takes about 3 to 5 days before we have the donor properly screened, if we have the stool bank where we have healthy stool samples donated by anonymous people who have been screened then that sample can be used. It’s just like what we do for blood banks or sperm banks or any other bank that we are creating.
That is what I was just thinking.
Dr. Dutta: I think there will be stool banks available in different hospitals. That is particularly relevant to people who are very sick, who need it promptly in the hospital, or those who do not have any relatives because the process otherwise can take about 5 days to a week before a donor is selected and a stool sample is collected.
That will be beneficial.
Dr. Dutta: I think that pretty much covers everything. Any other questions that you may have?
If they can’t get this treatment and their antibiotics fail, what then?
Dr. Dutta: If the antibiotics fail and one has a C. diff infection, it is a very scary thought because one is likely to become malnourished over a period of time, dehydrated, septic, and is likely to die or have the colon taken out. Taking the colon out is a very large operation and has its own morbidity and mortality, and if it happens to be in a patient who is above age 60 to 65 then there is a very high mortality of removing the colon.
Is it serious?
Dr. Dutta: It is very serious.
What are the symptoms?
Dr. Dutta: You are probably going to ask Ellen, but the symptoms are tremendous with abdominal pain, cramps, and diarrhea. Their life is completely out of their control. They have fecal incontinence also, meaning they soil their clothes; they can’t control anything. So, I think Ellen will tell you because she suffered from it for a long time.
How many other patients have been helped now?
Dr. Dutta: Many other patients and not only that, they also have hope now; they are not scared. Also, Dr. Bartlett has always told me that this is the answer to the problem. When I told him there is new antibiotic available he said that is not the answer because we have dealt with antibiotics for 35 years; just killing bacteria is not the answer. We have to grow healthy bacteria to get rid of this unwanted bacteria and I think that is a different approach and that is a paradigm shift in managing this disorder. We have always tried to kill the bad bacteria, but in this one we are not killing them, we are just wiping them out by growing some healthy bacteria and pushing them out and then don’t let them come back again.
END OF INTERVIEW
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