Emerging Disease and Zoonoses #15--Clostridium species

Species of the bacterium Clostridium have long been a scourge of humans. They are gram-positive, spore-forming bacteria that can be found in the soil around all of us. The spores then germinate when exposed to anaerobic conditions.

Clostridium botulinum is the cause of botulism, a serious and potentially fatal paralytic illness often caused by ingestion of contaminated foods. More recently, the bacterium has been used as the source of that anti-wrinkle miracle, BoTox: botulinum toxin type A, allowing all of Hollywood to smile without a wrinkly forehead (ah, the wonders of nature!). Clostridium tetani is the cause of tetanus, also known as "lockjaw". In both cases, death is ultimately due to paralysis of the muscles that function in breathing. While antibiotics such as penicillin can kill the bacteria, by the time symptoms appear, it's generally too late for such treatment: most of the symptoms are due to the toxins that these bacteria produce.

Some other Clostridium species have recently received a lot of attention as well. One I've discussed previously (moved over from the old blog) is Clostridium difficile. This is an intestinal bacterium that has long been a problem, but at a fairly low level. However, since 2000, rates of infection caused by C. difficile have soared, doubling in U.S. hospitals from 2000 to 2003, and jumping up another 25% in 2004. In a single decade in the U.K., the infection rate due to this bacterium increased over 20-fold. Mortality due to this bacterium also seems to have increased. Other changes in the epidemiology have occurred as well. Previously, serious infections due to C. difficile were generally limited to hospitalized patients who had taken antibiotics, as I mentioned in my previous post. Recently, however, these infections have been showing up in the community, and among those with no prior antibiotic exposure. The emergence of a new strain has also been suggested. From my prior post:

The emergence of a new, virulent strain [of C. difficile] was hypothesized, and that hypothesis was tested and confirmed in the reports by Loo et al. and McDonald et al., describing a new variant of this bacterium. This variant strain is resistant to fluoroquinolones, and contains an 18 base pair deletion in the tcdC gene. As this gene has been proposed to be a negative regulator of expression of the A and B toxins, it is likely that this mutation leads to the significantly higher toxin levels observed in these variants--reported to be 16 to 23 times higher than strains without the deletion.

Just as epidemic C. difficile emerged, another Clostridium species is also drawing the attention of public health experts. Clostridium sordellii is a rare and poorly understood bacterium. Overall, the risk of death from these infections has been estimated at 1 in 100,000. However, recently this bacterium has been linked to several deaths in young women following use of the drug RU-486 (mifepristone), the so-called "abortion pill" (not to be confused with "Plan B"). This drug is used as part of a two-step process to terminate a pregnancy (within the first 2 months). Mifepristone is administered and acts as a progesterone agonist, blocking the action of this hormone. Two days later, a second drug, misoprostol, is administered to induce labor and expel the fetus. At least 4 deaths due to infection with C. sordellii are being investigated by the FDA, and several others have been reported but have no prior history of using RU-486. As such, it appears likely that these deaths aren't directly due to any specific effects of RU-486, which was approved in the U.S. in 2000.

Identification of prior C. sordellii infections makes the case for a connection between RU-486 and C. sordellii even weaker. Combing through the literature, the CDC has identified 10 fatal cases of C. sordellii genital tract infection between 1977 through 2001. All but one was associated in some way with pregnancy: 8 of them following birth and another following a miscarriage. Currently, in addition to 4 deaths linked to RU-486, another potential case is being investigated that followed a miscarriage. Additionally, C. sordellii isn't the only Clostridium species that causes these pregnancy-related deaths: Clostridium perfringens, a common cause of food poisoning that rarely causes serious disease, has also been implicated. Therefore, it seems that pregnancy, not RU-486, is a key to these infections.

Finally, the link to zoonotic disease. C. difficile has also been increasingly found in animals, including as dogs:

A poodle involved in a hospital visitation program in south-central Ontario was discovered to be carrying the C. difficile bacterial strain that has caused severe epidemics of the disease in Quebec, parts of the United States and Britain, a team of Canadian researchers reports.

While the researchers are unclear how the dog became infected and whether it passed the bacteria to patients in the unnamed hospitals and nursing homes it visited, they said the finding suggests institutions should consider tighter rules for their pet therapy programs.

Transmission of the bacterium through the food chain has also been a concern, though that's not been clearly documented yet. However, when strains from several patients infected with C. difficile were analyzed, they appeared to be most closely related to animal isolates of the bacterium. How and when they entered the human population isn't certain.

As infections with these bacteria are increasingly in the spotlight, it's likely that we'll see more of them due not only to a real increase, but also due to reporting bias (in other words, you're much more likely to find what you're looking for than what you aren't). However, surveillance can only tell us so much. Clostridia are notoriously difficult to work with, making a better understanding of the bacterium via genetic manipulation a slow process. However, vaccines are in the works for the emerging Clostridia species, as well as drugs that bind to the toxins produced by C. difficile, and the NIH is urging research submissions on Clostridium. Again, as with chikungunya, these emerging organisms--particularly C. sordellii--are a minor cause of human morbidity and mortality at the moment, but this is the time to strike--before they cause huge outbreaks and a lot of human misery.