Brief History of C. Diff

In the early 1970's it was discovered that numerous patients who were taking clindamycin were getting diarrhea and colitis. At that time, clindamycin had been on the market for only a few years.

Larry Hoberman, Dick Norgaard, and Lannie Hughes, who were gastroenterology fellows, gathered data on 16 cases from Parkland Hospital, the Veterans Affairs Hospital, Methodist Hospital, and Baylor University Medical Center (BUMC). No pathogenic organisms could be cultured in any of these patients, and there was no evidence of staphylococcal overgrowth. All 16 patients had severe colitis, and 7 had pseudomembranous colitis. None had small bowel disease. The average age of the patients was 53, and 13 of the 16 were women. Four patients—25%—died.

Several possible etiologies were considered, including direct toxicity from or an allergy to clindamycin, bowel ischemia induced by the antibiotic, an altered bacterial flora, emergence of a new bacterial pathogen, and a virus. Since the physicians did not know the cause of the disease, they treated the patients as if they had ulcerative colitis. Fourteen patients received systemic steroids; 7, steroid enemas; 6, Lomotil; and 2, colectomies. None of the patients received vancomycin because they were not thought to have staphylococcal enterocolitis.

Within just a few years, C. difficile was discovered as the etiologic agent of antibiotic colitis. Ironically, C. difficile turned out to be sensitive to vancomycin, which might have been used in our patients had we not done tests to rule out staphylococcal enterocolitis.

C. difficile bacteria had been discovered years earlier, in 1935. In their attempt to understand the development of normal bacterial flora in neonates, Hall and O'Toole found a new anaerobe—which they called Bacillus difficilis because of the difficulty involved in its isolation and study. It wasn't pathogenic in newborns infants, but it was pathogenic in guinea pigs via a toxin. The bacillus has since been placed in the genus Clostridium. Although the spores are inactive, they can rapidly change into vegetative forms, which can then induce disease under the right circumstances.

C. difficile is resistant to most antibiotics. When a person takes an antibiotic, the normal colonic bacteria are reduced. Under these conditions, C. difficile is uninhibited by the normal bacterial products that tend to suppress it, and it has access to additional colonic nutrients. The C. difficile then proliferates. If it lacks the gene for toxin production, no disease develops. However, if it produces toxins A and B, it may cause colitis. The mechanism by which C. difficile toxins damage colonocytes is shown in Figure 2. The result of this damage is a loss of polarity of colonocytes, impaired cell migration, and cell death, which lead to colonic inflammation and in some cases pseudomembranous colitis.

C. difficile does not invade the colonic mucosa, and it does not cause disease if no toxin is produced. Even when a toxin is produced, some people become carriers or develop a mild, self-limited diarrhea while others develop severe colitis and may have multiple relapses of the disease. The clinical result depends on the briskness of the serum antibody response to the toxin. Aboudola et al showed that after infection with C. difficile, symptom-free carriers of the infection had a median of 3 enzyme-linked immunosorbent assay (ELISA) units per mL of serum IgG antitoxin A, and patients with a single episode of C. difficile–associated disease had 6 ELISA units. On the other hand, those patients with recurrent disease had only 0.7 units. Recurrent C. difficile colitis, then, appears to be associated with a lack of protective immunity to C. difficile toxins.

The serum antibody level to C. difficile can be increased with a vaccine, which is still experimental. In 2005, Sougioultzis et al tested the vaccine in three patients with serious, recurrent disease that was unresponsive to treatment. After vaccination, all three subjects had no further recurrence of diarrhea and were able to discontinue treatment with vancomycin. Further, in two of the three, the increases in serum IgG antibodies were striking: 3-fold and 4-fold increases in antitoxin A antibodies and 52-fold and 20-fold increases in antitoxin B antibodies. In 1997, researchers showed that passive immunotherapy with intravenous immunoglobulin was also effective in patients with impaired serum antitoxin response and refractory C. difficile colitis. The antibodies are believed to block the effects of the toxins until the normal flora can recover; the antibody effect is on the toxins and not on the organism itself.

Almost any antibiotic can lead to C. difficile intestinal disease. Diarrhea usually begins 4 to 9 days after the patient starts an antibiotic, but it can also develop up to 8 weeks after an antibiotic is discontinued. Generally, C. difficile disease is caused by genotypes and strains that are resistant to the precipitating antibiotic. Penicillins, the cephalosporins, and clindamycin are most apt to precipitate the disease. However, even vancomycin—which is effective in treating C. difficile disease—can cause the disease. This probably occurs because vancomycin suppresses both normal flora and the vegetative forms of C. difficile, but not its spores. When vancomycin is discontinued, the spores germinate and the new vegetative forms flourish in the altered bacterial environment.