- Now, over the past several years,
some of our colleagues, our colleagues in Mount Sinai
and in New York City have advocated the use
of antibiotics, the broad spectrum antibiotics,
for the care of IBD patients,
now, we would definitely have had some success with
some of your patients, perhaps the Crohn's colitis patients
being put on quinolone antibiotics,
ciprofloxacin for long term care.
That pretty much was a guarantee for all those individuals
to go on and contract C.diff.
The other issue that we've found is that
our patients who've undergone ileoanal pouch reconstruction,
the UC patients who've undergone J-pouch reconstruction
will often times need to be on antibiotics
as a way to control pouchitis,
that is a very, very high risk setting
for the contraction of C.diff
and our colleague, Bo Shen, at the Cleveland Clinic,
has actually seen approximately 19 percent of his
chronic pouch patients have gone on
to have problems with C.diff.
So, we presented this paper in combination
with Christian Stone's paper
from the Washington University in St. Louis,
and these were back to back publications
in Clinical Gastroenterology and Hepatology,
and I think I was a victim of no one wanting
to shake my hand for a few months after that
cause they immediately assumed that this was
an institution specific phenomenon,
and what we tried to do was show that this was perhaps
not something limited to only tertiary referral centers
and my colleague (mumbles)
who's an incredibly talented young man who's a
epidemiologist, as well as a gastroenterology trainee,
actually used the nationwide inpatient sample to
determine whether this phenomemon
was occurring in the United States.
So for those of you who are not familiar
with the nationwide inpatient sample,
this is basically a project that has been
funded by the National Healthcare Quality initiative
as part of the NIH.
It has discharge summaries from a thousand
short stay hospitals in the United States,
and there's roughly, approximately,
six thousand short stay hospitals in the U.S.,
so you have approximately one every five hospitals
that are pooling their data on discharge summaries
and you can query this and this is a
very good way to sort of confirm trends
that might be occurring at a national level.
So, sure enough, when we looked at this,
we saw that there was, again,
the doubling of C.difficile during this time period
from '98 onto 2004,
there was a significant rise
in the patients with Crohn's disease
and you see who were contracting C.diff
as it was coded on their discharge summaries,
but what we found most striking was the fact that
the IBD patients who had C.difficile
had a significantly increased mortality.
So, approximately four percent of the patients with
IBD admitted to a hospital in the year 2004
who contracted C.difficile died,
and if we actually start to do the math,
there were 118 confirmed C.difficile deaths
amongst the IBD population in 2004
and if we just multiply this up to get an estimate
of the events that are occurring in the United States,
we estimated that approximately 500 patients,
and this is a low estimate,
died as a result of C.difficile infection in the U.S.
Now I think it's important for us to sort of step back,
we are overly, perhaps preoccupied,
with certain issues in the inflammatory bowel disease world.
We are very concerned about
complications of immunosuppressive therapy.
There has been a huge initiative on our colleagues
in pediatrics to be very careful when it comes to use of
combination anti-inflammatory agents,
combinations of anti-TNF agents with immunosuppressants,
because of the potential for
very severe neoplastic complications, things like lymphoma.
So, correct me if I'm wrong,
I think we've had less than 30
hepatosplenic t-cell lymphomas confirmed
over the past decade plus in the IBD world.
We're having about 500 C.difficile
associated deaths annually since 2004.
So, if we do the math, we've got about 2,500
patients who have died as a result of this infection.
Now the problem is is that you're not gonna find it
unless you look for it,
and if you're dealing with an infection
that mimics an IBD flare,
where we're using broad spectrum agents
to basically blunt immunity,
you're really setting your patients up for trouble
and I think the biggest offender hit
is gonna be intravenous steroids.
The way the body clears a C.difficile infection
is by making a humoral immune response to
the toxin A, an IGg immune response to toxin A
and some of our most effective drugs in the world
for shutting down humoral immune responses are steroids.
So, the knee jerk reaction to admit a patient,
place them on high dose IV steroids,
I think is what has, unfortunately, precipitated this
very, very unfortunate reality.
So this is a quick review of the IBD
experience with C.difficile.
Patients with colitis are definitely the
group that are increased risk.
We actually did a multi-variant logistic regression
to show that maintenance immunosuppression was one of the
issues that correlated with
individuals who went on to get this infection,
so, basically, azathioprine, 6-MP, and methotrexate,
interestingly, anti-TNFs did not appear
to correlate with the C.difficile emergence.
This is something you have to maintain a high index
of suspicion because
10 percent of the cases that we saw in 2005
were new presentations,
they can actually occur concurrently.
Patients never heard of inflammatory bowel disease
and they're coming with C.diff and IBD at the same time.
The majorities are gonna be diagnosed as outpatients,
I believe our number was 78 percent of the individuals
were diagnosed within 48 hours of admission
which we interpreted to mean that this was a
acquired infection from the outpatient setting.
It can definitely be a contributing factor
in patients who have been in stable remission for years
and suddenly break through and become ill.
I definitely would recommend looking aggressively
for C.difficile in that setting.
Now making the diagnosis is problematic
and I'll show you in a few slides from now that
multiple stool samples for the toxin AB ELISA
are really required to feel confident
in terms of patient not having the infection,
and then the last bullet point here is
if you have a patient, in the outpatient setting,
who's not responding to metronidazole
consider the conversion to vancomycin.
If you have someone who's in inpatient,
I'd probably start with vancomycin
and there's gonna be good data
we can extrapolate from a nice randomized trial
that was performed in Canada that shows clear
superiority for vancomycin in patients
who are sick enough to require hospitalization.
So diagnostic considerations for C.difficile
in the IBD population,
unfortunately it's nonspecific,
we don't have easy clues sometimes that'll
tell us about this,
I think when we're waiting for leukocytosis to occur,
it's probably too late.
You know when you see a white count of 30 thousand,
we're gonna be in deep trouble, likewise,
and the albumin's falling,
these are all markers of someone going into,
heading down a very, very ominous path.
Radiographic studies are also nonspecific
until things are fairly far gone.
Endoscopic appearance, as I mentioned previously,
pseudomembranes are not gonna be present in the majority
of IBD patients and only about 50 percent
of the general population will demonstrate pseudomembranes.
The diagnosis is typically made in
laboratories that are the gold standard assay
is gonna be a cell culture toxin assay,
but this really requires a level of expertise
in the microbiology laboratories
to be able to grow this.
It's labor intensive, it's more expensive,
some hospitals have made the decision to go this route,
this is what we're doing at the University of Pittsburgh,
we've abandoned the toxin AB ELISA assay
is because of the lack of sensitivity,
but it's gonna be a much more,
preps more rare diagnostic approach.
The toxin screens are very effective when they're positive.
The problem is that the sensitivity is really not
as good as we would like
and it's very easy to do this
and it's less expensive, but, keep in mind that
the rate of detection is not what we would hope.
So this was our data from the 2005 cohort
and what we're looking at here is the
first, second, third, and fourth toxin ELISA assay.
Now John Bartlett has, from Johns Hopkins,
has recommended that a minimum of three toxin AB ELISAs
be sent to have approximately a 90 percent
confidence that you're gonna be able
to make the correct diagnosis.
So there's about a 10 percent false negative rate
in the general population.
What we found unfortunately that
it took four samples to have a false negative rate
of 10 percent in the IBD cohort.
Now in the inflammatory bowel disease population
I think we do have to remember that there are special
scenarios to keep in mind.
I already touched on the problem
with J-pouch reconstruction,
the ileoanal pouch reconstruction patients,
who are typically treated with antibiotics
is one of their major forms of therapy
and ciprofloxacin and other broad spectrum antibiotics
are often times the mainstay of people
who are suffering from chronic pouchitis.
So, approximately one in five patients
with chronic pouchitis maybe demonstrating C.difficile,
if we can extrapolate from Bo Shen's experience.
The other thing I would comment on is that
in patients who've had diverted segments of bowel,
people who've undergone a colectomy
and have a Hartmann's pouch left in place,
there is a report that C.difficile will colonize
the Hartmann's pouch and actually can have
a growth advantage in that environment.
So food coming through the GI tract actually functions
a prebiotic, it's actually the substrate
that allows bacterial populations to grow
and when the lower segments of the colon are diverted
that can create an environment where
anaerobes can sometimes have a preferential
advantage in terms of growth,
and when this occurs, it's really important to
use some form of topical therapy,
which typically means a vancomycin enema
and we do not have a metronidazole suppositories
available in the United States,
that's something that's available in Europe
only at this point.
Actually along that same lines,
it's important for people to know
that when you give metronidazole
for treatment of C.difficile,
it actually has to be absorbed and it comes through the bile
that's how it actually gets into the lower GI tract.
In a patient who has a,
someone who might've gone through surgical
interruption of their GI tract,
you're not gonna be able to get
antibiotic into that diverted segment of bowel
though the intravenous administration of drug
cause it's gonna be basically excreted through the liver
to ultimately get into the lumen,
so you have to use a topical approach in that setting.