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Update on C. difficile infection: From drugs to poop
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A well-known adverse effect of systemic antibiotic use is loose stools and diarrhea. This adverse effect can range from a mild inconvenience to significant fluid loss, dehydration and more serious consequences requiring hospitalization. Approximately 25% of all episodes of antibiotic-associated diarrhea result specifically from infection and illness by Clostridium difficile and its toxin.
The incidence of antibiotic-associated diarrhea (AAD) from C. difficile infection has increased significantly over recent years. Guidelines for diagnosing and treating C. difficile infection have been published for adults and children. In 2011, a new medication was labeled by the FDA specifically for treating C. difficile infection, in adults only. As well, additional studies are progressing in our experience and knowledge of the role of reintroducing fecal bacteria to the gastrointestinal tract as an additional means of treatment.
A policy statement by the AAP Committee on Infectious Diseases was published in 2013 in Pediatrics on diagnosing and treating C. difficile infection in infants and children. As data from controlled trials of children are very limited, these treatment guidelines are based upon adult data and guidelines. In 2010, the Society for Healthcare Epidemiology of America and the Infectious Diseases Society of America published adult clinical practice guidelines in Infection Control and Hospital Epidemiology, and the pediatric pharmacotherapy treatment guidelines largely mirror these adult guidelines.
When a child with C. difficile illness is receiving an antibiotic for treatment of another infection, the treatment antibiotic should be discontinued, if possible, and this alone may cause some episodes of AAD to resolve. Mild to moderate cases can be treated with oral metronidazole.
Edward A. Bell
Oral vancomycin is recommended for severe cases, with or without intravenous metronidazole. “Severe” is defined in the adult guidelines as leukocytosis or increasing serum creatinine concentrations. As this severity assessment is based upon adult data, the pediatric guidelines do not describe pediatric-specific severity assessment.
Metronidazole and vancomycin
Metronidazole is often used initially in an attempt to limit the development of resistance to vancomycin by other pathogens, such as enterococci. Some adult data from prospective and retrospective studies have compared the relative effectiveness of metronidazole and vancomycin. Recently published controlled trials in the adult literature demonstrate superior efficacy of oral vancomycin over oral metronidazole in severe episodes. Similar pediatric data, however, have not been published.
Practice guidelines recommend that first recurrences should be treated with the same agent that was used in the initial treatment. Further recurrences are best treated with vancomycin, tapered for pulsed-dosage regimens. This treatment recommendation also is based upon adult data, with several tapering or pulsed-dosage regimens available.
Recommendations for use of metronidazole in the adult guidelines are limited to one recurrence treatment course, as long-term use (ie, at least two recurrences) may result in neurotoxicity. This recommendation, however, is based upon a small open-label study (n=17) of adult patients given metronidazole for 2 to 4 weeks for non-C. difficile infections.
Other agents and probiotics
Several additional agents may be useful in treating C. difficile infection, although pediatric data to support their safe and effective use are very limited. These agents include rifaximin, nitazoxanide, and fidaxomicin. In 2011, fidaxomicin (Dificid, Cubist Pharmaceuticals) was labeled by the FDA specifically for treatment of C. difficile infection in adults. Fidaxomicin has been shown to be noninferior to vancomycin when treating mild to moderate disease, and it may be more effective than vancomycin when treating recurrences.
Last year a single case report on the successful use of fidaxomicin in a child aged 10 years was published. This child, with multiple medical problems including use of a gastrostomy tube, had suffered multiple recurrences of C. difficile infection and had failed a tapered vancomycin course. Further studies of fidaxomicin use in infants and children 6 months of age and older are currently in progress.
Probiotic compounds have been suggested by some as a logical treatment choice to replace and replenish gastrointestinal bacterial flora altered by antibiotic use, which allows C. difficile infection to occur. Although published pediatric data demonstrate a benefit of probiotic use in preventing AAD, very few data exist to demonstrate a benefit of treating active C. difficile disease with probiotics. A published single case report demonstrated some efficacy of treatment with a probiotic product containing Saccharomyces boulardii in a patient aged 22 months with Hirschsprung’s disease.
Fecal transplantation
Perhaps the most interesting and potentially promising therapy for treatment of C. difficile infection and disease is fecal transplantation. While fecal transplantation is not new — the first case report was published more than 50 years ago — it has recently shown renewed interest, and the first controlled trial was published in 2013 in the New England Journal of Medicine, demonstrating a significant benefit over vancomycin in adults. Other controlled trials in adults and children are currently in progress.
Previously published retrospective data and case series also have demonstrated high response rates of fecal transplantation (80% to 90%) in mostly adult patients. More recently, pediatric data describing the successful use of fecal transplantation have emerged, with publication of several case reports. In one of these case reports, six children, all of whom had failed multiple conventional treatment regimens (including metronidazole, vancomycin, along with additional treatments such as rifaximin, nitazoxanide, or fidaxomicin), were successfully treated with colonic-infused donor stool using a standard protocol.
In another case report, a treatment protocol of donor stool successfully administered by nasogastric tube was described in a child aged 2 years who had failed multiple treatment antibiotic and probiotic courses. These reports describe specific treatment protocols in detail. While these data on fecal transplantation are encouraging, many unknowns exist, including the most effective route of administration, standardization of donor samples and amount, and safety, among others.
Conclusions
Incidence rates of C. difficile infection and illness are increasing in children, and although guidelines for diagnosis and treatment in children and adults are available, more data specific to infants and children are needed. A new pharmacotherapeutic agent, fidaxomicin, has recently been labeled for use in treating C. difficile, although in the adult population only.
One of the most promising treatment strategies for C. difficile infection is quickly evolving, fecal transplantation, although many unknowns exist. As prevention may be one of the best strategies overall, an argument for the judicious use of antibiotics for all infants and children becomes even more persuasive.
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For more information:
Edward A. Bell, PharmD, BCPS, is professor of pharmacy practice at Drake University College of Pharmacy and Health Sciences and Blank Children’s Hospital and Clinics, Des Moines, Iowa. He also is a member of the Infectious Diseases in Children Editorial Board. Bell can be reached at ed.bell@drake.edu.
Disclosure: Bell reports no relevant financial disclosures.