C difficile-Related Diarrhea: Practical Pointers for Improving Diagnosis and Treatment

David A. Johnson, MD, FACG, FASGE, FACP

Disclosures

May 21, 2009

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Introduction

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Hello. I'm Dr. David Johnson, Professor of Medicine and Chief of Gastroenterology at Eastern Virginia Medical School in Norfolk, Virginia. Welcome to a new concept from Medscape called GI Common Concerns -- Computer Consult.

It's my privilege to be your host in this section. I'd like to walk through (as we look at this on a monthly basis) several common clinical problems that we see in gastroenterology as well as give you more of a "fireside chat" and advice on pragmatic issues that hopefully you can immediately apply to your practice.

Infectious Diarrhea and Clostridium difficile

Let's start with a very common condition that we deal with all the time. Diarrhea is not infrequent in my practice. The idea of infectious diarrhea as it relates to C difficile is one that we all think about, certainly in our inpatient practice particularly. If you're just seeing outpatients and patients who have been hospitalized, you should be thinking about this in all patients with diarrhea.

What is C difficile and why the buzz? It's because this is a very common problem. If you look at the current hospitalization rate, anywhere from 0.5% to 1% of patients in the hospital seem to come out with the diagnosis of C difficile. That's very different than what we see in the community because we've tied this infection to a couple of things, antibiotic exposure being the most common.

But, in fact, if you use community-acquired exposures for antibiotics, the relative risk for C difficile is around 1 in 5000. If you look at patients in the hospital, that risk goes up to 0.5% to 1% of all hospitalizations. We need to at least understand that C difficile is going to present, particularly in patients who have been hospitalized or in patients who have been exposed to antibiotics in the hospital.

Another factor that you need to think about is any immunosuppression in patients who have had a change in their microflora because of a bowel prep, particularly going into surgery, or even something as simple as a colonoscopy. The microflora shift may be enough to allow this bacterium to become more predominant. In fact, 1% to 4% of all "normals" have C difficile.

If you look at neonates, it's very common. For some reason, neonates don't seem to express the problems with C difficile infection. In adults, we still have a percentage of people who harbor this as a normal coinhabitant, and it's a balanced colonization that seems to exist.

Diagnostic Testing

Which patients do you really think about [when considering C difficile]? Certainly a patient who has been in the hospital and who now has diarrhea or who is in the hospital and currently has diarrhea. What do we do for these patients? We check their stools, right? We check them for a C difficile toxin, and we order a stool test for this.

Up until recently, these stool tests tested for 1 toxin, toxin A, which was thought to be the one that caused diarrhea. We know now that there are 2 toxins, toxins A and B. Most of the assays currently test for both toxins, but the sensitivity of these tests may be as low as 66%.

A negative test in the clinical scenario [in a patient] that you describe as being at high likelihood for C difficile or suspect for C difficile should never dissuade you from the diagnosis. In fact, in a patient who is very high-risk and certainly [in whom] you get negative testing, I would still treat that patient empirically.

There are ways to still check even more accurately for C difficile. Tissue culture cytotoxic assays are very specialized tests; they're anywhere from 100 to 1000 times more sensitive -- and they're doubly expensive. They're probably not very rapid in the return at most hospital settings; they typically take at least 48 hours to do. In community hospitals it may take longer because they'd be mailed out, so it may not be practical in this situation for you to ask for this type of testing.

So, you're stuck with a stool C difficile toxin assay. It comes back negative. In the appropriate situation I would repeat it, or, potentially, consider empiric treatment. If it's positive, then you're obviously starting to look at what to do for this patient.

Clinical Presentation and Treatment

The first thing I do is look at the clinical scenario and ask, is this patient really sick or is this patient just kind of sick?

For mild-to-moderate disease, I would start treatment with metronidazole at a dose of 500 mg orally, every 6 hours, for 10-14 days. In moderate or severe disease, metronidazole resistance is somewhat predictable and predictably higher. Oral vancomycin is the treatment choice, and the dose is 125 mg, every 6 hours, again for 10-14 days.

How do you predict who would have moderately severe disease? You can look at a patient and obviously if they're toxic, that's pretty much a no-brainer. If the patient is elderly, that [age] qualifies as a risk factor for more severe disease. If patients also have a white count of over 15,000, if their albumin is less than 2.5, or if they have a temperature of over 101, 2 of those 4 factors are clinical acumen factors that you can use to say that this is more severe disease and is more likely to have a metronidazole resistance.

When you prescribe vancomycin for your patient, it should be oral, because it's got to have a topical effect in the colon. IV metronidazole, however, does have some effect because it's secreted in the biliary system and then excreted into the bowel. So an IV metronidazole will work. IV vancomycin has zero preventive benefit or treatment benefit for patients with C difficile.

For oral vancomycin, I'm going to give you a tip: When you send the patient to the pharmacy for vancomycin, 125 mg every 6 hours for 14 days, that's about a $1200 ticket for that oral therapy. That pill or capsule is actually a nongeneric and it is something that's extremely expensive. It's anywhere from $15 and upwards per capsule. Now, the tip is to work with your pharmacy. Get them to compound this. Take the IV vancomycin -- take a gram. Have them compound that in a liquid formulation. It doesn't taste very good, but they can put some sweetener in this. They can then take a gram and make 8 doses of this in a liquid formulation. The half-life or shelf life of this you'll have to work with your pharmacy in compounding, but that dose now costs approximately a dollar.

If you're not doing this, you really need to be. Think about the cost savings. We have about a 15-fold-plus cost reduction per dose. Patients now take this incredibly cheap medication, oral vancomycin, as an IV formulation compounded, delivered over the course of the same timeframe. If you're not doing this, you really should be. It's a tremendous savings and certainly of equal efficacy.

Refractory/Relapsing Patients

What else should you know about C difficile? If there is a treatment, you need to worry about the patients who are "refractory" to treatment. If you're treating somebody who you think may be refractory, what do you do?

For somebody who is not getting any better on metronidazole, I would switch them to vancomycin; I think that's pretty easy for us to justify.

If you have a sick patient in the ICU, oral vancomycin and IV metronidazole would be the combination [to use] because now you're getting biliary excretion of metronidazole and the oral vancomycin. If you're treating a patient who has an ileus, recognize that they may not get the oral medication down to the colon.

You can actually administer the vancomycin and give this in a rectal administration. Mix 500 mg in a 100-cc saline enema and deliver this rectally every 6 hours. So it's a way that you can get this dose to the patient.

The more severe the patient illness is, the more likely they're going to need higher doses. With a really toxic patient, I would give them 500 mg every 6 hours orally. If they had a severe ileus, I'd have them on IV metronidazole and vancomycin (rectal administration).

What do you do as far as probiotics? You hear a lot of noise about this. There is very good evidence, at least suggested, that we can prevent or diminish C difficile with probiotics. The one probiotic that really has been studied is very similar to brewer's yeast; it's Saccharomyces boulardii.[1] It's not something that you necessarily go out and get at your local pharmacy. Lactobacillus also has been used.

I use these agents in my practice; they are sometimes very inexpensive relative to the overall toxicity of the disease. I'll couple these with antibiotics.

Bile salt agents, like cholestyramine or colestipol, have not been well studied by themselves. In choosing a sole treatment for C difficile, I would not advise bile salt agents. They do help with diarrheal patients and they do bind the toxin, but you must separate this from any oral administrating antibiotic because they will bind that antibiotic.

One of the simplest things to do if you have a patient who has C difficile is to stop the antibiotic. If a nontoxic patient has C difficile, stopping the antibiotic -- and this is particularly in an outpatient setting -- will make the antibiotic-related diarrhea resolve about 25% of the time. So that's treatment in and of itself.

About 20% of people with C difficile will relapse, so you need to forewarn them. If they've had 1 relapse, the rate goes up to 40%. If they've had 2 relapses, the rate goes up to 60%. They should always be forewarned if they start to have recurrent diarrhea. I wouldn't mess with testing these people as much as I would get them started on therapy, because their likelihood for multiple relapses is quite high.

One of the ways to treat these relapses is to go back and use the same antibiotic. It's very unusual to have refractory or relapsing C difficile be related to antibiotic resistance. So if I treated them with metronidazole upfront and they got better and then relapsed, I would treat them again. Metronidazole is very inexpensive and is relatively easy to use. [Remember the tip about vancomycin cost savings above.]

I don't use vancomycin on the mild cases; I think there are significant resistances to vancomycin emerging. In particular, we see this with vancomycin-resistant Enterococcus. So I wouldn't throw vancomycin around lightly.

If somebody comes in with relapsing C difficile, we move to a tapering regimen. This particularly goes with vancomycin; 2 studies have looked at this and have tapered the patients after a 14-day course of vancomycin.[2,3] Instead of 4 times a day, [patients are put on it for] 3 times a day for another week, and then 2 times a day for another week, and then once a day for a week, and then every other day for another week. The relapse rate seems to be diminished with that tapering regimen and seems to be quite effective.

In my particular experience, in looking at one study that has done this, oral rifaximin has been very effective in patients who are deemed "relapsing and refractory"; this is an agent that seems to have a very nice effect on C difficile.[4]The MICs [minimum inhibitory concentrations] are quite strong, and it does not seem to breed resistance in any way. Rifampin is another drug that's been used. I've not had any experience in using that. I choose rifaximin as my go-to if I find that patients are having problems with C difficile that is refractory or relapsing on vancomycin.

Novel Treatments

There are a couple of novel therapies that I'll share with you just as a discussion point. One of them is fecal repopulation -- oral-fecal recolonization. Normal feces are taken from a healthy adult and are then administered down an NG [nasogastric] tube to hopefully recolonize with healthy bacteria.

I invite you to discuss that with your patients the next time you're talking about C difficile therapy. I don't think there's a lot of traction with that, but it has been used in some patients who really are deemed "refractory." I've not had any experience with that; I've not had the need to do that in my practice.

Other Problems to Be Considered: Toxic Colitis

One caveat is that in a patient who presents with severe ileus, is hospitalized, and [has] lactic acidosis and abdominal distention, [it is important not to] forget C difficile.[In this scenario the patient] may not present with diarrhea, which is the hallmark for C difficile, but in the setting of toxic colitis, which is sometimes very possible with C difficile, you have to remember, even in the absence of diarrhea, you should consider C difficile.

[In this situation] I would begin empiric therapy for if you're not going to do at least some diagnostic testing by a toxin assay or sticking a scope up there and looking for pseudomembranes. There are rare occasions; I've had 2 patients over the last 3 years who have actually gone to surgery because of toxic megacolon from C difficile. So it does happen, and you need to consider this.

Home Care

A final caveat is in patients when they go home. You need to recognize that even healthy patients can get C difficile. We've talked about hospitalized patients, patients who have been on antibiotics or immunosuppressants, and patients who have maybe had some purgatives and altered their microflora. When you send a patient home with C difficile or the patient is at home [already], you need to counsel them about hygiene. Hygiene in particular for C difficile is critical in the hospital, and it's most important to wash your hands with soap and water.

C difficile spores are resistant to temperature and to drying and, in fact, [it is resistant] to a lot of the [alcohol-based] antimicrobial agents that hospitals now provide us with to wash our hands. So simple handwashing with soap and water is very important.

When the patient goes home, there are a couple of things I tell them: They need to have a dedicated bathroom. They need to get some bleach and water; I have them mix 10-to-1 water to bleach (household bleach is fine) and wash the toilet after each use. They should wash the counters the same way after each use because [C difficile] is something that can spread to household individuals who are healthy. Again, they need to be counseled accordingly.

Conclusion

C difficile is a very common problem. The more we're sanguine and understanding in how we can deal with this, the better we can make our patients. Don't forget the tip about vancomycin. I think it's a real cost savings. I bet your patients are going to come back and say, "Thank you, Doctor" when they do comparative costs.

I look forward to another session with you. Hopefully I've given you some pragmatic issues -- and now answers -- for dealing with your next patient who has diarrhea and perhaps C difficile. I look forward to our next conversations and discussions. I'm Dr. David Johnson. Thanks for listening.

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