The evolving picture of Clostridium difficile-associated disease suggests that we may need to revise our traditional approach to the child with persistent diarrhea.
The increase in frequency and severity of health care-associated Clostridium difficile-associated disease (CDAD) in North America over the last several years is believed to be due in large part to a newer, more virulent strain first reported a little over a year ago (N. Engl. J. Med. 2005;353:2433–41, 2442–9)
At the same time, we've been seeing previously healthy patients without prior antimicrobial use, including children, become infected in the community. Of 23 community-acquired cases reported to the CDC from four states during May and June of 2005, 11 were in children less than 18 years of age (MMWR 2005;54:1201–5).
In a 3-year prospective study published in the fall of 2006, 7% of 1,626 stool samples from children who presented to an emergency department with diarrhea were positive for C. difficile toxin (Clin. Infect. Dis. 2006;43:807–13). It's not clear from the data whether this represents an increase, but we do know that it's a problem.
I think we need to consider the possibility of CDAD in any child—even those without prior antibiotic use—who has persistent diarrhea lasting more than 5 days, or very severe diarrhea of more than 8–10 stools a day. The data suggest that about 1 in 10 of these children will have stool assays positive for C. difficile toxin.
Some children with CDAD—perhaps 25%–35%—improve on their own within a week and may not need treatment. The ones whose condition does not resolve in a week are candidates for metronidazole therapy. About 15%–20% of those treated will fail. For them, the American Academy of Pediatrics advises a second course of metronidazole. For the 15%–20% who will fail or relapse a second time, oral vancomycin is recommended.
While you're waiting for the toxin assay to come back, I think it's a good idea to use probiotics such as Lactobacillus GG species or Saccharomyces boulardii as a preemptive strike, even before you know the pathogen. Data suggest that those “good bacteria” might be helpful in restoring balance in the flora and thus reduce symptoms due to a variety of diarrhea-causing organisms, including rotavirus and other viral agents as well as C. difficile (Am. J. Gastroenterol. 2006;101:812–22).
Because alcohol-based hand sanitizers aren't as effective at removing infectious C. difficile spores from contaminated hands, it's important to wash your hands with soap and water after examining children with prolonged diarrhea. However, until you know what the pathogen is, use of alcohol-based products also is recommended because they're better at eliminating other GI pathogens including the usual virus suspects. I will typically wash with soap and water first, dry my hands, then rub in the sanitizer as I'm walking away from the sink after seeing children with persistent diarrhea and an as-yet undefined pathogen.
The appearance of CDAD in previously healthy, community-dwelling individuals is a new and worrisome change. Until recently, antibiotic use was believed to be the nearly universal culprit that disrupted the natural gut flora and allowed C. difficile to flourish, leading to the presentations ranging from frequent diarrhea to the characteristic pseudomembranous colitis.
Now, however, it appears that in some children CDAD may be initially triggered by a common viral gastroenteritis—such as rotavirus, norovirus, or adenovirus—which lowers the colonic pH enough to prompt the normally-quiescent C. difficile to begin overproducing toxin.
This recent shift may be related to the newly described strain, which not only produces many times the usual amount of C. difficile toxins A and B, but also contains a mutation that leads to the production of an additional binary toxin that appears to be even more toxic to gut mucosa than are A and B. We don't fully understand the implications of this new strain. It is becoming clear, though, that it's not a temporary situation as we had hoped.
On the positive side, several ongoing trials offer some reason for optimism. A group at Baylor College of Medicine in Houston is now conducting National Institutes of Health-funded phase III trials of nitazoxanide in adults with CDAD. Nitazoxanide (Alinia, manufactured by Romark Laboratories L.C., Tampa, Fla.), which acts by interfering with anaerobic metabolic pathways, is already licensed for the treatment of parasitic diseases of the gastrointestinal tract, such as giardiasis, and has been used in millions of children worldwide. So far, the CDAD data look good.
A totally different approach to CDAD treatment is with a nonabsorbable polymer called tolevamer, manufactured by Genzyme Corp., Cambridge, Mass. It works by binding C. difficile toxins A and B. Because it's not an antibiotic, tolevamer would be expected to avoid the problems associated with antimicrobial treatment, including resistance. Phase II data suggested that it worked at least as well as vancomycin and was associated with less recurrence of diarrhea, although there was an increased risk for hyperkalemia (Clin. Infect. Dis. 2006;43:411–20). Genzyme expects to complete phase III trials this year. The agent has been given fast-track designation by the Food and Drug Administration, and the company anticipates commercial approval in 2008.