Question & Answer

Children’s PSC Question & Answer – With Dr. Yinka Davies

Frequently Asked Questions as discussed in Teleconference with Dr. Yinka Davies on the Use of Vancomycin to Treat Children with Primary Sclerosing Cholangitis (PSC) May 18, 2011.

Note about the teleconference:
This teleconference was organized by Jenny Wunderly for parents who have kids with PSC (Primary Sclerosing Cholangitis). The teleconference was held to give parents an opportunity to learn more about the Vancomycin Study being conducted at Stanford University. Dr. Yinka Davies joined Dr. Kenneth Cox‘s study as a fellow in 1994 and follows more than half of the study patients in her clinic at Sutter Hospital in Sacramento. Thirty-nine parents called in to take part in the call. The following is a summary of the discussion, edited by Rachel Beadle. For further information, please send us an email.

The Safety of Vancomycin

Q: Have there been any cases of resistant bacteria due to the long-term use of vancomycin?
A: To date, nothing has been reported with oral vancomycin and VRE. VRE has been reported with IV vancomycin, but not in oral vancomycin. And we do check in with ViroPharma to whom everything gets reported. I know that becomes a big concern and a big scare for people. I’ve heard it in conferences when I’ve presented. However, since there hasn’t been a case of VRE with oral vancomycin yet, we believe the risks are probably small for developing VRE with this form of the drug. Can we guarantee that somebody won’t get VRE? Absolutely not, and we do put the risk of VRE in our consent forms. If we did start seeing cases of VRE with oral vancomycin, it would probably be a big deal in a larger sense because vancomycin is used to treat C. diff. I’m hoping to get more information from the studies that we’re doing on gut flora. I think the data coming out will guide us, and tell us more about what vancomycin is doing.

Q: How would vancomycin interact with immunosuppressant meds?
A: Down the road, if you were on vancomycin and it didn’t work for your child, and you ended up needing a transplant, immunosuppresants would still work, because they work on a different mechanism and pathway.

Q: How harsh is vancomycin on the stomach? Have any children (particularly young ones < 10yrs) experienced pain from the vancomycin treatment?
A: We haven’t had kids experiencing pain on vancomycin. Vancomycin is a bactericide affecting bacteria in the gut, so it works on gram positive bacteria. I had one patient who was nauseous at first, but wound up adjusting and doing well on vancomycin. Our youngest patient was two years old when he started, and has done well.

Q: Does taking vancomycin make you more susceptible to any other illnesses/diseases? Besides the usual liver enzyme level tests, do you screen for other markers during the course of the treatment? Which ones and why?
A: We do screen for other illnesses. We haven’t seen any more susceptibility to getting illnesses while taking vancomycin. The kids have done great on it. We screen the liver enzymes, inflammatory markers, auto-immune markers, and CN19 which is a precursor to biliary cancer. Stool studies and saliva studies are taken on some of these kids before they start with vancomycin. We monitor the labs monthly. We look at CN19 yearly, which is so important because PSC makes you more susceptible to biliary cancer.

Q: Have any children experienced side effects from taking vancomycin?
A: We haven’t had any side effects.

Q: What other risks are associated with the oral vancomycin treatment?
A: Again, we haven’t seen any so far with vancomycin. We consent for the usual things any drug can cause, like rashes and headaches. We also consent for VRE, which, again, we haven’t seen.

Q: We don’t have prescription coverage for oral vancomycin, so I use IV vancomycin and put it in a capsule. Do you have any comments or concerns about the administration of vancomycin in this way?
A: The IV concentration is OK to be taken orally. In fact, that’s how we’ve done it with some of our pediatric patients. For some of the little kids who cannot take a capsule, we give them the IV vancomycin orally.

The Effects of Vancomycin on Bacteria

Q: Does vancomycin kill all gut bacteria and negate the effect of probiotics?
A: Vancomycin is a bactericidal drug that inhibits cell wall synthesis of the bacteria, so it kills it off certain gram-positive bacteria. Vancomycin affects C. diff and Staph in particular, and that’s what it has been used for. It will not kill off all the bacteria because there are gram-negative and other gram-positive bacteria that are not sensitive to vancomycin. Vancomycin will kill off some probiotics, but it doesn’t interfere with antibiotics as far as we know. Does it negate the effect of probiotics? Some. Any antibiotic will kill off some of the probiotics, but not all. With our patients in the study, we pull them off of the probiotics at the start of vancomycin, so we can limit the variables involved in the research.

Q: If, while taking vancomycin, my daughter gets an ear infection, will it interfere with an alternate antibiotic?
A: No, but if anyone is going to start another antibiotic we always have them check in, just so we can monitor their labs and clinical situation at that time.

Q: There has been a lot of interesting research on the possible role of the micro biome on diseases like UC and PSC. How far along is this research, in your opinion? Any chance we’ll see therapeutic options emerge anytime soon?
A: It is not very far along, so we don’t have a lot of answers on it. But our techniques are better and we are looking more and more at microbials and getting more answers. 8. Other Medicines and Supplements used to Treat PSC

Q: Do you recommend any dietary modifications or use of supplements that might help to slow the progression of PSC, or help to manage its effects on the liver? (Parent mentioned her son had his gallbladder out and could not eat a lot of fat without getting pain).
A: I’m a big believer in probiotics, so I use them quite a bit, and I use probiotics in our IBD patients. I haven’t used them a lot in our PSC patients at the start, but I do have some patients who are on them after they have been on vancomycin for quite some time. We use some dietary modifications with some of our Crohn’s patients, particularly the Specific Carbohydrate Diet (SCD), and we have seen that it has been affective. But we haven’t tried it in PSC patients. On our Crohn’s patients we will eventually look at their gut flora to see if we can get any answers as to why they respond to a complex carbohydrate diet which excludes simple carbohydrates. [Parent] Dr. Davies, do you recommend one type of probiotics over another? [Dr. Davies] I use VSL#3. I use it because I saw a patient during my training who had significant diarrhea and didn’t seem to get better, so we tested her stool, and they said she is only growing one bug. She actually had no staph, no yeast, nothing else. I tried every kind of probiotic. I eventually tried VSL#3 which was not available here at the time. I got it from Italy, and it made a big difference in this patient.

Q: Do you know anybody anywhere in the world who can cure this disease? Or at least halt the progression? I don’t care if the treatment is FDA approved or not.
A: I don’t know of anyone who can cure it. There is lots of research going on, though I’d have to say that we are probably the closest to halting the progression of the disease. We’ve biopsied these kids and we’ve seen that vancomycin is working. I had a patient who was transplanted about 6 years ago for PSC. She showed up with jaundice and liver failure. She needed a transplant urgently. She did remarkably well post transplant, but 3 years after her transplant, her liver enzymes went up. There was a big debate on whether this was PSC or rejection. A biopsy showed that it was PSC. We decided to put her on vancomycin. Her liver numbers dropped. We looked at all her labs at all stages and compared them. With vancomycin, the PSC was gone. The fibrosis was gone. I am hoping to publish about her case in the New England Journal, because this will be the first case where a transplanted patient with PSC improved while taking vancomycin. So when I see these results, I have to say that we are probably the closest to at least stopping the progression of the disease. But I hope someone can find a cure for this.

Vancomycin and its Affect on other Autoimmune Disorders

Q: Is there a possibility that vancomycin may also work in the treatment of other autoimmune cases? To what extent are UC and Crohn’s symptoms managed by vancomycin in the vancomycin study?
A: We’ve used vancomycin on patients with just UC and Crohn’s, who do not have PSC, and haven’t seen any improvement at all. We will collect stool studies and lab work — once we are in a better funding position — on just UC and Crohn’s patients to gain an understanding of why vancomycin may not have worked on them. We have seen improvement of colitis symptoms with patients who have both IBD and PSC. I think all of our PSC patients are off of all other medicines and are managing their IBD symptoms with vancomycin. Many of the patients newly enrolled in the new study are coming to us already on other medication. We’ll leave these patients on their drugs while they start vancomycin. We monitor our patients for their IBD during the study. We do colonoscopies after one year on vancomycin and we do fecal wipes and monitor their labs throughout the study.

Q: Will vancomycin also heal an inflamed gall bladder?
A: I don’t know if it will, because we haven’t looked at that. I would assume if there was an inflammatory process that was similar to the inflammatory liver process of PSC, then you might see that.

Q: Has vancomycin been successful with AIH overlap syndrome?
A: I don’t have any patients with both PSC and AIH. I don’t know if anyone has used vancomycin on those patients. Overlap between PSC and AIH is seen more often in the adult world, so we may get more data from the adult studies on this. Dr. Shah at Stanford is looking at the adult patients with PSC. 10. Vancomycin Protocol.

Q: How long do the trials on the vancomycin medicine last?
A: We just extended our study out to 5 years. There are also patients taking vancomycin who are not in our study that we follow. Some of these patients have been on vancomycin for a while.

Q: After the trial is over, can my daughter continue on vancomycin, or does she have to go back on Urso?
A: Absolutely. Kids can stay on vancomycin after participating in the study. I think the driving force will be accessibility to the medication. It depends on whether we can get it for patients from ViroPharma, the maker of vancomycin.

Q: Can you review the treatment protocol. (ie, dose/day, ongoing testing requirements/frequency, etc.)?
A: The dose is 50mg per kilogram, up to 1,500mg per day. It is taken as 500mg 3 times a day. We take labs and stool studies monthly. We do a biopsy and a colonoscopy at a year.

Q: How do you work with Dr. Cox?
A: I’m his fellow. We communicate by e-mail every day, and we usually talk about 3 or 4 days per week. Dr. Cox is very vested in the study. Dr. Cox came up with vancomycin as a treatment for PSC, and this epiphany that he had has changed so many lives. I work with him very closely. Dr. Cox has been involved with a lot of patients that I have followed, and he gets to meet the families at the conferences/fundraisers that we do.

Treating Mild or Asymptomatic Cases of PSC with Vancomycin

Q: If a child now has normal LFTs and is asymptomatic, is there any point in trying vancomycin? Any drawbacks or concerns in doing so? Will treating with vancomycin halt the progression at this early stage? How would we monitor the response?
A: Yes. It would be good to start vancomycin on patients in the early stages of PSC. There are far too many kids who show up with cirrhosis at young ages. Because we don’t understand a lot about the progression–how fast the progression will occur, and which patients it will move fast in–it is good to start vancomycin early. But I am biased. I work with children on vancomycin and I see how well they are doing. I do not work with any other drug, so for me it is vancomycin right from the start.

Q: Is it possible to determine the optimal time to start vancomycin in a child without symptoms, whose LFT’s have normalized with urso, and who is considered between stage 1 & 2 of PSC?
A: There is no correlation between LFT numbers and the progression of the disease. You can have normal enzymes and cirrhosis. The true test is what it looks like under the microscope. The way I practice is to put myself in the position of the parent. If this were my child, what would I do? If this were my child in this situation, I’d be on vancomycin.

Q: For a new diagnosis of PSC, with no Ulcerative Colitis and no Crohn’s Disease, what would you do in that case?
A: I would check immune markers, like ANCA and ASCA to see if there are any IBD markers, and if there were I would consider treating with vancomycin. We had a patient who showed up with liver disease, and ended up getting a liver biopsy, but there was no Colitis. Unfortunately, they ended up getting part of the bowel in the liver biopsy. When looking under the microscope we saw colonic tissue that should not have been there and luckily the child did well. However, we saw that part of that colonic tissue was inflamed. Sometimes things are missed during a colonoscopy.

Q: In cases that are very mild of PSC, where MRCP is normal, and the liver is still healthy, does it make sense to hold off on taking vancomycin until the vancomycin study has progressed further (has more participants followed for a longer time)?
A: I have seen too many cases of improvement to recommend holding off on vancomycin in even the mild cases. However, as I mentioned earlier, I have a strong bias in favor of using vancomycin. I have had too many PSC patients show up to me with cirrhosis. We even have a patient who has cholangiocarcinoma. I just don’t think we have the answers on how fast the disease can progress in an individual. We don’t have any predictors. Even your liver enzymes cannot predict that. I think that with mild disease, this is the time to go on, because once the MRCP starts to show inflammation, you are already beginning to develop scar tissue. That would mean that it is now starting to sclerose. So I would say that it is best to start patients on vancomycin when their symptoms are still mild, which is actually the scenario for a lot of our kids. In fact most of the patients taking vancomycin in our study have normal MRCP’s.

Working with Local Doctors to Treat Children with Vancomycin

Q: What can I do to convince my doctors to consider vancomycin as a treatment option?
A: Dr. Cox or I can speak to the doctor. That has helped in a few cases. There have been some instances where patients have contacted us about the use of vancomycin, and have found that their local GI’s or liver specialists are reluctant to try the drug to treat PSC.

Q: Why do you believe so many hepatologists are negative about the vancomycin treatment? What do you think it will take to turn more into believers?
A: It has been tough and there has been a lot of skepticism amongst doctors. But we are now getting more data, and doctors are coming on board. While I can’t be absolute sure how vancomycin will affect an individual patient, I think it is a phenomenal option compared to what’s out there right now. Do we need more answers? We absolutely do. So I understand some of the reluctance to embrace vancomycin. But I don’t agree with them on doing a clinic trial with controls. Not with our pediatric patients. I have two children myself, and the last thing I would want in a situation like ours is to know one of them was getting a placebo with a drug that has worked across the board. This isn’t a drug that has worked with only 25 percent of our patients. This isn’t a drug that we try and see that patients are not getting better. This is a drug that we’ve used and seen remarkable success with our patients. When we look at the facts of this drug and the downsides of it, I think that everything points to putting kids on vancomycin. I hope that with more data and proof coming in, doctors will at least look at the possibility of trying it. We see doctors readily try drugs like remicade, which has been associated with Lymphoma. But here is a drug (vancomycin) that hasn’t been associated with any side effects, and that has worked well. Yet we see so much reluctance in the use of it. As we treat more patients and get good results, I hope that more doctors will consider the medication for their patients. Right now we have about 16 more kids whose families contacted us about using vancomycin, and they came to us by word of mouth. Some of them heard about vancomycin through our foundation, or through the website. A lot of families do their own research and find out about the vancomycin study that way. I just hope we can reach more of these kids.

The Use of Vancomycin in Patients with PSC who do not have IBD

Q: Are children who have PSC, but do not have IBD, eligible to go on vancomycin? If not, why not?
A: They are eligible to join the study. Including these patients in our study would give us more data to understand why they did or did not respond to the drug. It would help us understand what the pathogen is in their gut, and why they don’t have colitis. I think the more patients we get in that spectrum, the more answers we are going to have to better target exactly what is going on.

The Relationship between PSC and other Autoimmune Disorders

Q: What is the relationship between children with PSC and Parents with autoimmune disease?
A: There definitely is a genetic predisposition for developing autoimmune disorders in families with close relatives with these disorders. However, we don’t know the exact link yet between PSC and a predisposition for other autoimmune disorders in families. Hopefully more data will bring some answers to that.

Q: Have you ever seen any relationship between relatives who have Celiacs and/or Eosinophylic Esophagitis and relatives who have PSC?
A: Yes, because they are all auto-immune processes. So again, there is a genetic predisposition to develop all these types of diseases.

Follow-up Questions

Q: Do you have any children that you are treating for biliary cancer, as this can be a long-term complication of PSC, particularly in adults?
A: I personally don’t, but Dr. Cox has a patient who he diagnosed with biliary cancer a few weeks ago. We screen for CA-19, which we believe should be checked yearly, at the minimum. CA-19 can indicate the presence of biliary cancer.

Q: Some families are interested in trying vancomycin with their children but are encountering some resistance with their doctors about using the drug to treat PSC. What do you suggest they do? Should they consider switching doctors?
A: I have been in situations like this before. Once doctors are able to speak to either Dr. Cox or myself directly, they are usually more comfortable about trying the medicine with their patients. I haven’t had anyone say to me “nope, I’m not interested”, after a conversation. We had a case where we spoke to a doctor who was initially resistant about using vancomycin with his patients, and decided to try it after speaking with us. He later wound up sending three more of his patients to us. As doctors, we all get patients coming to us who have done their own research and found things on the internet. And we are not always sure about the reliability of the information people are finding. Doctors may not understand what our study is about. Some doctors have thought that we are keeping patients on IV vancomycin long-term, and are not aware that we are using the medicine orally. So, unless they hear the information directly from us, there may be a lot of misperceptions. You already have a relationship with your doctor, so I wouldn’t suggest switching. Once we speak to the doctors and they have a better understanding of our study and use of vancomycin, they tend to feel more comfortable trying vancomycin with their PSC patients.

If children join the study, we discuss everything with their local doctors. The first thing we do is speak to our families and their doctors on the phone and get consent. Then we come back and conference with the doctors again on the phone, so we really need them to be on board with us. And, as GI doctors, they are interested as well. These are diseases we have had no answers to and we are starting to see the answers.

Q: Once patients have been on vancomycin for a while and are stable, would you recommend starting them on probiotics?
A: I would. I never say no to probiotics, except when patients first start with the study, just because we want to control the variables. But for children who have been on vancomycin for a while, I think it is fine for them to start taking probiotics. I like VSL#3, and Culturelle is another great probiotic. Some patients I have treated have not responded to Culturelle, so I prefer VSL#3. With VSL#3, I prescribe 450 billion a day, which is one packet.

Q: Does vancomycin eradicate the probiotic?
A: To some degree it does. It will take away some of the gram-positive bacteria. But there are many other bacteria in there that are helpful. I believe strongly that having a good mix of bacteria in the gut is necessary. It is interesting, for instance, that with the Specific Carbohydrate diet alone–which changes the growth of bacteria in the gut—patients see improvement. We still don’t have all the answers, but I think we are on the right pathway by examining and changing the gut flora.

Q: If I want to try to get my child into the vancomycin study, would you recommend holding off on taking probiotics?
A: Yes, I would recommend holding off on taking probiotics if your child may be joining the study. If anyone comes to us on antibiotics or probiotics, they have to stop taking these, and we have them wait two months before starting them on vancomycin.

Please contact the Children’s PSC Foundation if you would like an expanded version of the transcript.

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