Emergence of epidemic Clostridium difficile

Clostridium difficile has joined MRSA, SARS, avian influenza, and West Nile as a hot new emerging disease. This bacterium, a cousin to Clostridium tetani-the causative agent of tetanus--and Clostridium botulinum--the botulism bacterium--is a spore-forming anaerobe. Carried by about 3 percent of healthy adults, the bacterium is generally present as a metabolically inactive spore. The bacterium typically causes problems in the nosocomial (hospital) environment, where up to 40 percent of hospital patients may be colonized. Clinical disease generally presents as watery diarrhea and cramps, and is the most frequent infectious cause of nosocomial diarrhea, resulting in about 3 million cases per year. Mortality is generally low (less than 3 percent). Though not commonly fatal, these infections have a high monetary cost: each infection results in ~$3600 in excess health care costs, for a total of over $1 billion in the United States alone every year.

Ironically, it is antibiotic treatment that often precipitates manifestation of disease. In the 1974, a study by Tedesco et al showed that, in 200 patients given clindamycin, 41 developed diarrhea, and 20 had pseudomembranous colitis, a pathological finding characteristic of infection with C. difficile. Indeed, in the 1970s, the most common antibiotic associated with C. difficile disease was clindamycin; cephalosporins in the 1980s; and, in 2 new papers published in the New England Journal of Medicine, fluoroquinolones.

Like other disease-causing Clostridia, C. difficile produces a repertoire of toxins. Toxins A and B, released by the bacteria after colonization of the gut, are thought to be the main cause of disease pathogenesis. These toxins cause illness by disrupting the cytoskeleton of fibroblasts.

An increase in both the rate and severity of C. difficile infections has been noted since the 1980s--what underlay this increase? The emergence of a new, virulent strain 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 be16 to 23 times higher than strains without the deletion.

This isolate has been found not only in the US, but also in Canada, where it was responsible for 100 deaths over an 18-month period in a Quebec hospital. Additionally, analysis of the pulsed field gel electrophoresis (PFGE) patterns of 6000 historic isolates show that this variant has been present in hospitals dating back at least to the late 1980s. It is thought that the recent increase in incidence is due to increasing use of fluroquinolones. For instance, in one hospital studied in Pennsylvania, increase in disease incidence was correlated with a switch from levofloxacin to moxifloxacin; however, in another hospital, levofloxacin was found to be used in the largest percentage of patients who developed infection with C. difficile.

These outbreaks--again--underscore the need for active surveillance for infections. In a hospital situation, infections can be controlled by using careful procedures to avoid exposing non-colonized patients to C. difficile. Patient care equipment, including blood pressure cuffs and stethoscopes, should be used either only for the colonized patient, or thoroughly cleaned before using it on a second patient. Additionally, health care workers need to use actual soap and water to wash their hands between patients, as alcohol-based hand sanitizers aren't effective in killing C. difficile spores. Finally, in the past, outbreaks of C. difficile disease have been controlled by restricting the use of antibiotics associated with disease outbreak--a difficult proposition for fluoroquinolone antibiotics. Therefore, we must be careful to use them in a more judicious manner--something microbiologists have long called for, anyway. Finally, as a greater percentage of our population is being housed in nursing homes and other long-term care operations, this is a problem we're unlikely to see vanish anytime soon, unfortunately.

Further reading:

McDonald et al.. 2005. An Epidemic, Toxin Gene-Variant Strain of Clostridium difficile. NEJM, 353:2433. Link.

Loo et al.. 2005. A Predominantly Clonal Multi-Institutional Outbreak of Clostridium difficile-Associated Diarrhea with High Morbidity and Mortality. NEJM, 353:2442. Link.

Bartlett and Perl. 2005. The New Clostridium difficile -- What Does It Mean?. NEJM, 353:2503. Link.

Anonymous. 2005. Severe Clostridium difficile--Associated Disease in Populations Previously at Low Risk --- Four States, 2005. MMWR. 54:1201. Link.