Clostridium difficile was first described over 75 years ago by Hall and O'Toole, and initially named 'Bacillus difficilis' not because of its virulence but rather because of the difficulty culturing the bacteria ex vivo. They found that this bacteria asymptomatically colonized 40-70% of neonates within the first month of birth. In fact, c-dif is a slow-growing, indolent bacteria whose morbidity has been unleashed exclusively by iatrogenic eradication of gut flora by (you guessed it) doctors. It turns out that c-dif's relative inactivity makes it insensitive to most standard antibiotics; therefore when a patient is treated broadly with a penicillin, cephalosporin, or fluoroquinolone for a pneumonia or cholecystitis, the coast becomes clear for c-dif to spread and do its damage. The damage is done primarily by thenefarious work of 2 toxins, appropriately named c-dif toxin A and toxin B (CDTa and CDTb, respectively). These toxins disrupt the actin cytoskeleton-stabilized tight junctions between intestinal epithelialcells via UDP-glucose-dependent glycosylation and inactivation of Rho and Ras protiens, leading to epithelial sloughing and subsequent inflammation.
Over the years, the liberal use of antibiotics in hospitals has driven increasing virulence of c-dif, such that a hospital stay of 2 days or longer now results in a 10% risk of contracting c-dif colitis. The risk appears to be highest in the elderly, possibly because of their impaired immune response. This virulence began to progress to the point that c-dif outbreaks began to emerge in the community and in absence of recent antibiotic therapy, first in Hungary in 2004 but quickly in the US by 2006, and particularly in patients on gastric acid-suppressive therapies.
One of the main concerns with controlling c-dif infections is the frequency of recurrence (20-33% after the first infection, 65% or higher in those with more than 1 occurence). And while c-dif colitis is treatable with either metronidazole or vancomycin, antibiotic efficacy decreases in subsequent recurrences. Recurrent c-dif appears to be more virulent based on upregulation of CDTa and b toxins; yet this may also be a key to its treatment. One of the fun things about emerging therapies for c-dif is how 2 of the most promising therapies are about as different as can be: recombinant humanized monoclonal antibody therapy versus....someone else's poop.
The high-tech answer: passive and active immunization.
The first hint that the immune system might be of some help in fighting off recurrent c-dif came from a study in 2000 published in the New England Journal. In it, Kyne and colleagues showed that patients who had c-dif colonization without infection had high serum levels of antibodies against toxin A. They followed it up with a study published in Lancet one year later in which they showed that following acute c-dif infection, the patients who were 'immune' to recurrence made IgM antibodies against toxin A within 3 days. Similar results were later shown for c-dif toxin B. It took about 6 years for fully humanized monoclonal antibodies to be made against both toxins and shown to protect hamsters from recurrent c-dif (Infect Immun. 2006, 74(11): 6339-47).
4 years later, in 2010, a landmark study published in NEJM showed that administration of mAb against both toxins A and B resulted in a relative risk reduction of 70% in patients with 1 episode of c-dif colitis and 80% in patients with more than 1 prior episode. The inherent problem with this strategy is that it provides only passive immunity, and therefore patients would require frequent infusions. A more lasting solution would be to induce active immunity in patients with vaccination against target peptide antigens. In 2003, a vaccine composed of immunogenic portions of toxin A was able to induce significant titers of IgG in patients, and case reports of 3 patients with severe recurrent c-dif colitis showed that two out of three patients who were vaccinated generated high titers of antibodies to both CDTB and CDTA and induced remission without recurrence. A phase II trial in patients aged 18-85 with 1+ prior episode of c-dif colitis is currently underway.
The low-tech option: your poo, please.
The other potential solution to c-dif is simple, logical, fairly gross, and impressively efficacious. It goes by the name of "fecal flora reconstitution," which is a fancy way of saying "poop transfusion." It's based on two major ideas: first, that patients who succumb to c-dif infections have not only a poor immune response to c-dif, but commensal gut flora that don't protect them against c-dif overgrowth, and second, that the best way to overcome a deadly, but frankly wimpy bacteria like c-dif is to re-introduce a set of much more competitive gut flora. Thus: poop transfusions. It's simple; check the donor for communicable diseases as well as a history of c-dif exposure, liquefy their feces in non-bacteriostatic saline, dump it into a colonoscope, administer the donor feces at the level of the ileum, have the patient take immodium to maximize contact time between the new flora and the gut epithelium, and watch the magic happen.
And, for the most part, it does. Almost every study, despite variability, demonstrates sustained responses in refractory patients with only one dose in >90% of patients, and response to a 2nd dose in the majority of the 10% of patients who don't respond initially. The point? if you can get over slightly stomach-turning concept, its an incredible, cost-effective solution to an iatrogenic problem. And its sure to make one bond in your life stronger - after all, once you share poop, what can't you share?
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I'll leave you this election night, in which 4/10 voters verbalized support for the "death panel" touting Tea Party, with the thoughts of David Meltzer of the University of Chicago's department of Medicine and Economics, on the need to accept rationing for what it is (a fact of life in the health care system) so that we can have some real debate, not over whether we should ration (a healthcare system without it is ludicrous) but rather, who should be in charge.
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