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Celebration of the 30th Anniversary of Clostridium difficileA summary of selected presentations from the 9th Biennial Congress of the Anaerobe Society of the Americas
More than 300 participants from 30 countries gathered in Long Beach, California from June 24–27 to hear the latest on anaerobe-related topics, ranging from probiotics for prevention and treatment of infections to the possibility that autism is due to an infectious disease. Special tribute was bestowed to Dr. Sherwood Gorbach (Tufts University School of Medicine, Boston, MA) and Dr. John Bartlett (Johns Hopkins University School of Medicine, Baltimore, MD) for their seminal roles in delineating the association between pseudomembranous colitis and Clostridium difficile colonization of the gastrointestinal tract. Their now-classic paper, published in the New England Journal of Medicine in 1978 (Bartlett, et al.), also established the cytotoxic cell culture system as the gold standard method of testing for presence of the etiological agent in stool. Dr. Bartlett began the C. difficile portion of the program with an historical perspective on the early years of initial detection of the organism and subsequent changes in diagnostic methods and treatment. After its discovery, epidemiological studies soon revealed that numerous infants less than one year old could be asymptomatic carriers of toxigenic C. difficile, hence the recommendation to avoid testing for C. difficile in children less than one year old. He stated that enzyme-immunoassay has largely replaced cytotoxin assays for diagnosis in most U.S. laboratories not because it was better, but because it was easier to perform, cheaper and yielded faster results. Interestingly, vancomycin was originally the treatment of choice but over the next decade metronidazole gained favor similarly because it was cheaper and because of fears of encouraging vancomycin resistance in other organisms. Recent experience however, suggests that vancomycin is indeed the preferred treatment. Finally, Bartlett mentioned that new data from David Relman’s laboratory at Stanford University (Dethlefsen, et al.; Eckburg, et al.) illuminating the length of time that the bowel flora are perturbed by antibiotics has prompted him to create a unique new treatment regimen using pulsed dosing of vancomycin for six weeks. The next two speakers explored virulence factors of C. difficile. Dr. Gayatri Vedantam from Loyola University in Chicago, IL reported that the recently emerged hypervirulent NAP1 (North American Pulsed-Field type 1), also called PCR ribotype 027 or restriction endonuclease analysis type BI (“bee-eye”) strains, have 100% higher adherence to human intestinal epithelial cells than related non-hypervirulent strains. This adherence is mediated by surface protein A. This information could serve as the basis for development of new therapies. Because of increasing numbers of the hypervirulent strains, from 5.7% in 1999 to 23% in 2007 (Redelings, Sorvillo, and Mascola), there has been expanding interest in virulence factors. Dr. Dena Lyris from Monash University, Victoria, Australia, described the role of Toxins A (enterotoxin) and B (cytotoxin). New genetic tools have allowed better dissection of the toxin genes, and her studies revealed unequivocally that Toxin B is the major virulence factor. In conventional strains, toxin production results from starvation conditions in the stationary phase of growth. The BI strains produce 16 and 23 times the normal levels of Toxins A and B respectively, in all growth phases. These strains also produce a binary toxin, whose role in virulence is not yet known. In response to the question of why this strain has spread so rapidly, she mentioned that other studies point to increased spore production, and thus to an increased environmental reservoir as one factor in the rapid spread of the hypervirulent strains throughout western Europe and the U.S. Dr. Cliff McDonald from the Centers for Disease Control and Prevention in Atlanta, GA, discussed the changing epidemiology of C. difficile infection. Data from hospital discharge summaries suggest that there were 100,000 cases in 1992, and around 300,000 in 2006. More than half of reported cases occur in long-term care facilities. If more reliable data from an Ohio-based study are extrapolated to the entire U.S., there are 500,000 cases/year and 23,000 deaths. Costs including 180 day follow-up after hospitalization are estimated to be from $3800 to $7200 per patient, or more than $1 billion/year in the U.S. C. difficile infection accounts for a 2.8 day average increased length of stay (Dubberke, et al.). The attributable mortality is 5.7%, but those who survive are more likely to be discharged to a nursing home. Another factor that is likely contributing to the rapid spread of the BI strain is its increasing resistance to fluoroquinolones (FQs) in a time of increasing use of FQs worldwide. Substitution of one FQ for another (from levofloxacin to gatifloxacin, for example) is unlikely to control an outbreak (Gaynes, et al.). Some improvement has been noted when FQs were removed from the formulary altogether (Dubberke, et al.). Dr. McDonald stated that the risk of acquisition rises four-fold if more than one patient on a ward has C. difficile infection. Both infection control measures and antibiotic restrictions are needed for optimal control. Although the expanded use of alcohol gel hand washes has been postulated to contribute to the increase in C. difficile infections, institutions have not shown an increase in C. difficile rates coinciding with alcohol gel use. According to Dr. McDonald, the use of alcohol gel and increasing C. difficile cases are probably unrelated. Dr. Brandi Limbago from CDC next discussed the changing mix of strains in the U.S. after the hypervirulent strains suddenly erupted in six states starting in 2005. Her most recent study revealed that 83% of cases were healthcare related and 17% community related. Approximately half of both groups were NAP1 or hypervirulent strains. Dr. Limbago also reported that strains associated with outbreaks affecting pigs in pork production facilities are moving into the human population. The keynote address by Dr. Abraham Sonenshein from Tufts University began with an explanation of the mechanics of spore formation and germination. One characteristic that is exploited in culture methods is the encouragement of vegetative growth from spores by taurocholate or by thioglycolate and lysozyme. Taurocholate is now a component of the most sensitive media formulations used for cultivation of C. difficile from stool. In the bowel, the normal flora produces compounds from bile that are inhibitors of germination. Antibiotic therapy lowers the formation of such secondary bile compounds, leading to increased C. difficile germination in the gut. Dr. Peter Gilligan, University of North Carolina, Chapel Hill, NC, presented a summary of current laboratory testing options and his recommendations for laboratories today. Recent data from College of American Pathologists proficiency testing surveys showed that use of immunochromatographic tests for toxin has increased from 26% of laboratories in 2004 to 46% in 2008, whereas enzyme immunoassays for toxin A alone usage has dropped from 18% to 2%. Unfortunately, the gold standard test, cytotoxicity and neutralization in cell culture is performed by only 1% of all U.S. laboratories. After the cytotoxicity test, the next most reliable results are derived from toxigenic culture. Unfortunately, the results take at least 48 hours, too late for clinical decision-making. According to Dr. Gilligan, the most cost-effective algorithm today is to perform an initial screening test with the C. diff Quik Chek® (TechLab, Blacksburg, VA) glutamate-dehydrogenase (GDH) test and reflex all positives to a reference test such as cytotoxin. The source of the GDH test does make a difference, with certain products yielding unacceptably low sensitivities. Studies published by Ticehurst and colleagues from Johns Hopkins University Medical Center showed that compared to an immunoassay for toxins A and B with sensitivity of only 38%, the GDH screen had a sensitivity of 100%, so no potential cases were missed with this system (Ticehurst, et al.). Dr. Lance Peterson, Northwestern University in Evanston, IL, highlighted current and future molecular methods for detection toxigenic C. difficile. With the newly developed GeneOhm system (Becton Dickinson), two pre-clinical trials have shown better sensitivity than the GDH screening methods (average 96% vs. 79% for GDH). Dr. Peterson stated that once excellent and rapid PCR tests are available, it is imperative for the physician to be educated as to which patients to test (those with >= 3 loose stool per day) and then to use the most sensitive test first. He noted, “PCR appears to be that technology.” Additional presentations followed by Dr. Dale Gerding, VA Hospital, Hines, I.L. on antimicrobial therapeutic options and Dr. Johan Bakken, St. Luke’s Infectious Disease Associates, Duluth, M.N. on non-traditional therapies, particularly the controversial but highly effective fecal transplant therapy. Finally, Dr. Sherwood Gorbach summarized the state of the art and outlined the continuing challenges faced in order to respond to the rising epidemic of CDI. References
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