Current Understanding of the Dominant Strains of <i>Clostridium difficile</i>

Peter L. Salgo, MD: Are all Clostridium difficile the same? That is, to say, in terms of cultures. Are there various strains? Do these strains have various toxicities? Is one Clostridium difficile better than another? If you’re going to have Clostridium difficile, which would you like?

Dale N. Gerding, MD: It is clear that all Clostridium difficile are not the same. Prior to about the year 2000, I think most people viewed Clostridium difficile as somewhat of a nuisance illness. It was not as devastating as it is today. Part of the reason that we’ve seen a marked increase, 3 times as many cases now of Clostridium difficile in the United States, is due to a strain that appeared around the year 2000. It goes by a complex name of BI/027 and NAP1—which [are] just different ways of classifying typing. That strain spread from the United States to Canada, into Europe, and has caused a marked increase in Clostridium difficile rates and in Clostridium difficile mortality. It accounted for as many as 30% to 60% of all cases in the United States in the early 2000s. It is now declining in the United States, and the CDC, this year for the first time, reported that the NAP1 strain is no longer number 1. It has been surpassed by a strain called ribotype 106. But this strain possesses 3 toxins: A, B, and then a binary toxin. And it’s thought that the binary toxin is contributing to the severity of illness with this strain. The strain type really does make a difference, and clearly, I’ve never seen as severe of a disease as I started to see when we started finding this strain.

Daniel E. Freedberg, MD, MS: There are a few factors that make this strain more virulent than other strains. One is that it seems to make more toxin than other strains. Another is that it has innate resistance to fluoroquinolones. So, patients receiving fluoroquinolones are at increased risk for getting this NAP1 strain.

Peter L. Salgo, MD: Antimicrobials are selecting out, leaving the Clostridium difficile alone. This one is more left alone than the other ones. It’s more likely than it was before…

Daniel E. Freedberg, MD, MS: Certainly, in patients who receive fluoroquinolones and in both the community and even more so in the hospital setting, this strain is, if not number 1, certainly among the most common.

Peter L. Salgo, MD: Fluoroquinolones are ubiquitous, right? You call your doctor and you say, “I’ve got a cold.” The doctor may, in fact, give you a pack of fluoroquinolones to take for however many days.

Yoav Golan, MD, MS: And fluoroquinolones can actually be associated with any type of Clostridium difficile—not just this strain. Interestingly, this strain may also be associated with higher recurrence rates, which is one of the main issues. It is unlike any other infection and also may be less responsive or treatable by some of the antibiotics that we’ve been using. There has been some data that show that there may be a higher resistance rate for this strain with metronidazole, which is one of the most commonly used anti-Clostridium difficile antibiotics. And that may be also one of the factors that contributes to the severity of disease. As you know, when we have patients with Clostridium difficile, we don’t have a culture. We don’t have susceptibility testing. Physicians treat it with less guidance as compared to other infections.

Peter L. Salgo, MD: But you do have PCR (polymerase chain reaction). You have genetic analysis.

Daniel E. Freedberg, MD, MS: Yes, we do have a PCR, but the PCR is just for the toxin B gene. It doesn’t tell you what strain of Clostridium difficile it is. One of the things I’ve always wondered is why there isn’t more vancomycin resistance to Clostridium difficile. Why, with all the use of oral vancomycin, hasn’t it developed?

Peter L. Salgo, MD: Anybody know? We use vancomycin like water.

Erik Dubberke, MD: Actually, to develop vancomycin resistance, it requires several genes. It’s not like a single-point mutation; it’s a pretty complex mechanism. At this point, I’m not aware of Clostridium difficile that are inherently resistant to vancomycin, which might facilitate a gene transfer event to Clostridium difficile. And part of it is also the levels of vancomycin we give in the colon. Even with 125 mg, 4 times a day, which is the standard treatment dose of vancomycin, you’re getting levels of vancomycin in the colon that are probably at least 500, if not 1000, times higher than you need to kill Clostridium difficile.

Lawrence J. Brandt, MD: Are you familiar with metronidazole resistance?

Erik Dubberke, MD: In vitro, metronidazole resistance has not been described, but part of the caveat there is that the metronidazole susceptibility breakpoints are based on serum levels of metronidazole, not the amount of metronidazole that you get in the colon—which is several-fold lower than what you get in the blood, is highly variable, and also decreases over time as the inflammation resolves.

Peter L. Salgo, MD: And it’s also definitional, right? Resistance is really a gray scale. You’re resistant when you have X number of dilutions of an antibiotic that no longer inhibits bacterial growth, but if you give enough, maybe it will. So, to some degree, you’ve got to define what you mean by resistance. Nothing necessarily is completely, absolutely resistant. Although some may be.

Yoav Golan, MD, MS: But it’s only one determinant of success of therapy, and it is important to remember that even though there is no resistance to vancomycin per se, not everyone is treated adequately or is being cured. And, in fact, when we talk about the consequences in mortality, this is despite adequate therapy.