Risk Factors for Developing <i>Clostridium difficile</i> Infections

Peter L. Salgo, MD: We’ve all been talking about exposure to antimicrobial agents. Which agents are the worst offenders? Which ones do we really need to be careful of? And in taking a history from somebody with diarrhea, which antibiotics would you ask about, for example?

Lawrence J. Brandt, MD: First of all, any antibiotic, essentially, can do this—can be associated with Clostridium difficile. And, yes, there are high-risk antibiotics and low-risk antibiotics. The highest, as was mentioned, would be the fluoroquinolones and the cephalosporins; and the lower risk antibiotics would be the sulfa drugs and penicillin. I would need an infectious disease person to help guide me through the exact number, but the lists of these are quite available. The antibiotics are given to a person, and the person is as important as the antibiotic. So, what people do we have to be especially careful about?

With regards to people, the most important risk factor is age. Every disease has its magic “old age.” Old age for Clostridium difficile is 65. Above age 65, you don’t do as well with the disease as you do below 65. But then there are other diseases—patients with inflammatory bowel disease are at particular risk, patients with particularly severe disease, especially ulcerative colitis. Patients with chronic kidney disease are at particular risk take longer to get rid of the disease. Patients with chronic liver disease are at risk, and so are the patients who are immunosuppressed either by a drug such as an immunosuppressive agent, biologic agent, or prednisone, which also increases the mortality of the disease. You can have patients who have diseases that make them immunosuppressed&mdash;diabetes, HIV, organ transplantation. So, those are the people and those are the antibiotics that make the risk.

Peter L. Salgo, MD: Let me just be clear: Are you saying that over age 65 you get Clostridium difficile more often? Or when over 65, if you get it, you do worse?

Lawrence J. Brandt, MD: I think that probably both of those are true.

Peter L. Salgo, MD: I was afraid you were going to say that.

Lawrence J. Brandt, MD: You get it more often. You don’t fight the infection as well. Your white cells don’t fight the infection as well. They can’t kill the bacteria as well.

Daniel E. Freedberg, MD, MS: If you look at the population incidence rates stratified by age for Clostridium difficile infection, and you see the rates in the highest age brackets (adults who are over 75 or 80 years-old), and you compare them to the people who are in the lowest age bracket (people in their 20s), the rates are 100-fold different. So, patients who are older get Clostridium difficile more and they do a lot worse when they’ve gotten Clostridium difficile.

Peter L. Salgo, MD: It occurs to me, as I’m listening to you list these things, that the one common thread is immunocompetence, or immunodepression—diabetes, liver disease, chronic kidney disease. Growing older, your immune system doesn’t work as well. All of these things seem to correlate to decreased immunocompetence.

Daniel E. Freedberg, MD, MS: Well, I think we can almost step back and say, “What are the fundamental things you absolutely need to get Clostridium difficile?” And there are 2 things: You need exposure to the organism; if you’ve never been exposed to the organism, you can’t possibly get it; and then, you need to have some fundamental problem in the host microbiome. If the gut is normal, and if the bacteria in the host gut are able to resist the expansion of Clostridium difficile, you won’t get Clostridium difficile. So, all of these risk factors really are things that fundamentally impact the health of the normal gut microbiome—immunosuppression; old age, perhaps, along with all the other problems of old age; a less resilient microbiome. So those key things are what facilitates the development of Clostridium difficile.

Lawrence J. Brandt, MD: I think that’s an important point, but I don’t think that’s been proven. It’s a very good postulate. We’re talking about the microbiota and the intestinal microbiota for almost every disease that we can mention today. But, careful studies of the microbiota, in different situations of disease, are only now being started. Although what you’re saying, I believe to be true, I don’t think it’s really been proven.

Yoav Golan, MD, MS: I think there is more direct evidence. There have been some observations that correlated the ability to mount immune responses to the toxin, and show that it may be associated with a high risk of developing Clostridium difficile in other circumstances with a recurrence. And more recent data from a clinical trial actually showed that people who had lower antibody levels were more associated with development of Clostridium difficile and recurrence.

We know that, with age, you’re less likely to develop an antibody response. And this is a very practical aspect of Clostridium difficile because, as we move forward, we’re going to see immune type of solutions, or possible solutions, for Clostridium difficile in terms of passive immunity or active immunity (such as vaccines).

Peter L. Salgo, MD: We’re going to talk about that, too, but I don’t want to let the topic of traditional risk factors and 2 additional classes of drugs go. Everybody thinks “antibiotics,” but then we’ve got the proton pump inhibitors and the histamine-2 (H2) blockers. If you’re on those drugs, you’re more susceptible to Clostridium difficile. How does that work?

Daniel E. Freedberg, MD, MS: There have been a lot of epidemiologic studies linking proton pump inhibitors (PPIs) and other acid-suppressing medications with Clostridium difficile infection. These are observational studies, so this isn’t based on the best quality data.

We did a study where we gave PPIs to healthy volunteers. We checked their stool before and afterward, and what we found is that PPIs didn’t act like antibiotics. They didn’t wipe out the gut microbiome. They changed the gut microbiome just a little bit. They did decrease some non-Clostridium difficile clostridial species. So, perhaps there are organisms that are competing with Clostridium difficile for the same resources? But, probably, it explains why PPIs are a modest risk factor for Clostridium difficile infection. I don’t think that they’re at the level of antibiotics, and the epidemiologic studies bear that out.

Dale N. Gerding, MD: That’s theoretically possible, but we think most people get Clostridium difficile by ingesting spores. Spores are highly resistant to acid. You don’t need to neutralize the acid for a spore to get through your stomach.

Peter L. Salgo, MD: I’m confused again.

Dale N. Gerding, MD: The PPIs do have antimicrobial activity. They are helicobacter drugs with MICs (minimum inhibitory concentrations) for Helicobacter. It wouldn’t be surprising, at all, that they would also affect part of your microbiota—which you were able to document.

Daniel E. Freedberg, MD, MS:Or it’s possible, but not proven, that they have other, more subtle effects. Earlier, it was mentioned that the bile acids are an important determinant of how well Clostridium difficile germinates—how well it goes from the spore form to the vegetative form. So, it’s possible, but definitely not proven, that PPIs may act at that step or another step.