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C. difficile: Difficulties in treatment and a potential role for fecal transplants
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Infection and disease with Clostridium difficile have increased in children and adults in recent years. Use of antibiotics is an important risk factor for the development of C. difficile infection, and C. difficile is the most common cause of antibiotic-associated diarrhea. Guidelines on the diagnosis and treatment of CDI have recently been published, and new therapies have been investigated.
Several risk factors increase the likelihood for development of CDI and diarrhea: previous or concurrent use of antibiotics; use of proton pump inhibitors (eg, omeprazole); use of nasogastric, gastrostomy or jejunostomy tubes; and underlying bowel disease or surgery, among others. The identification of new, possibly more virulent strains of C. difficile, such as NAP1, has complicated treatment efforts. Up to 25% to 30% of patients treated for CDI will experience at least one recurrence. Individuals with repeated recurrences can be especially difficult to treat.
Recently, evidence-based guidelines on the diagnosis and treatment of C. difficile have been published. In 2010, the Society for Healthcare Epidemiology of America (SHEA) and the Infectious Diseases Society of America published clinical practice guidelines for adults. This year, updated guidelines were published to supplement these guidelines. Also this year, the AAP Committee on Infectious Diseases published a policy statement on CDI in infants and children. Because there are no data from controlled trials in infants and children, treatment recommendations for infants and children are largely based upon adult data and recommendations.
Treatment
If an infant or child who is taking an antibiotic develops CDI, recommendations call for discontinuance of the antibiotic, and this alone may result in resolution of infection and diarrhea. Frequently, however, additional therapy is necessary. Metronidazole is recommended as initial therapy for mild-moderate disease and for treatment of a first recurrence. Vancomycin can be used initially for severe disease or for a second recurrence. Comparative efficacy data on metronidazole and vancomycin in adults (there are no equivalent pediatric data) from controlled trials generally indicate that these two agents are equally effective. Some data, although not strong, suggest that vancomycin may be more effective for more severe disease.
Additional reasoning that supports use of metronidazole as initial therapy is the drug’s significantly lower cost, as compared with vancomycin. Use of the reconstituted IV dosage form of oral vancomycin can reduce costs, although some children may complain of the product’s taste.
Edward A. Bell
Recurrence of CDI can occur and be difficult to treat and resolve. Beyond its use for treatment of the first mild-moderate recurrence, metronidazole should not be used further because continued use may result in neurotoxicity. Two or more recurrences require more complicated treatment regimens. Vancomycin given as tapered or pulsed regimens can be used, according to the SHEA/IDSA and AAP guidelines, but no specific regimen is recommended.
Although other pharmacotherapeutic agents have been mentioned as possible alternatives for recurrent infection, no pediatric data exist to support their use. Few adult data support the use of nitazoxanide (Alinia, Romark) or rifaximin (Xifaxan, Salix). Only one agent has recently been labeled for use specifically to treat CDI, fidaxomicin (Dificid, Optimer). Fidaxomicin is not labeled for use in children younger than 18 years and is expensive ($175 per tablet).
Fecal transplants
Perhaps the most interesting, and certainly most non-appealing, treatment to be investigated for recurrent CDI and disease is fecal transplantation. Although not a new concept (the first case report was published in 1958), data from several case-report series, several systematic reviews and a newly published controlled trial are providing more information on the potential role of fecal transplantation as treatment for recurrent CDI.
As can be imagined, the concept underlying the role and efficacy of fecal transplantation is repopulation of normal gastrointestinal bacterial flora. Alteration in normal bowel flora from antibiotic use or other means of disturbing the gastrointestinal environment may afford C. difficile an opportunity to cause clinical infection. Most data from case-report series on fecal transplantation result from use in older adults, although some, limited pediatric data exist.
Published data from these case-report series include approximately 300 patients. Three systematic reviews of these reports have recently been published. Gough published a review of 317 patients from 27 case-report series and concluded that fecal transplantation was highly effective and resulted in disease resolution in 92% of patients involved in the study.
Guo concluded from an analysis of seven case-report series of 124 patients that fecal transplantation was safe and effective. These systematic reviews, however, have been criticized for poor methodology.
Kassam more rigorously evaluated published data on fecal transplantation that evaluated 273 patients from 11 studies. Of these 273 individuals with recurrent CDI, fecal transplantation resulted in clinical resolution in 245 patients (89.7%). In this review, lower gastrointestinal instillation (colonoscopy, enema) demonstrated some benefit over upper gastrointestinal instillation (nasogastric tube). Data assessed in these reviews are limited because they were produced from non-controlled evaluations.
In addition, these data are limited because of the wide variance and non-standardization of the treatment regimens, including route of administration; volume of fecal material administered; method of fecal material preparation; and donor source, among others. Authors of these reviews have concluded that controlled trials are warranted.
New data available
Recognizing the need for controlled studies, van Nood and colleagues published the results of the first controlled study of fecal transplantation earlier this year. In an open-label, non-blinded manner, 43 adult patients were randomly assigned to oral vancomycin, oral vancomycin plus bowel lavage or vancomycin plus bowel lavage followed by fecal transplantation by nasoduodenal tube.
Inclusion criteria were non-critically ill or immunocompromised adults who had a relapse of CDI after at least one course of vancomycin or metronidazole. The primary endpoint was the resolution of diarrhea without relapse after 10 weeks. As most patients in the two control groups had relapse, the data and safety monitoring board recommended early trial termination. Of the patients in the randomized group to receive fecal transplantation from an anonymous donor, clinical disease resolved in 81% (13/16) after the first infusion. An additional infusion from a different donor resulted in resolution in two additional patients. Of the control groups, clinical resolution occurred in 31% (4/13) of patients who received vancomycin alone, and in 23% (3/13) of those who received vancomycin plus bowel lavage. Besides the controlled study, two additional controlled trials are currently recruiting patients.
From a pediatric perspective, the data and studies described are limited by the inclusion of adult patients. How these data apply to children is unknown, such as effective dosing and route of administration. In the systematic review by Gough, several case-report series evaluated included some children aged as young as 11 years.
Perhaps the most informative report is from Russell and colleagues, who described the successful use of fecal transplantation for treatment of CDI in a 2-year-old patient. After treatment of relapsing disease with metronidazole, vancomycin, probiotics, rifaximin and nitazoxanide, fecal transplantation by nasogastric tube using the child’s father as the donor was initiated. Using a modified protocol adopted from published adult patient data, fecal transplantation was successfully administered to this child.
Conclusions
Infection and disease from C. difficile are increasing, and although evidence-based guidelines have recently been published, very few data have included infants and children. Metronidazole and vancomycin are likely to effectively treat C. difficile in most, although recurrences can be problematic. A new agent, fidaxomicin, was recently approved for use in adults, but no data support its safe and effective use in infants or children.
Fecal transplantation appears to be a promising therapy for relapsing infection, but many unknowns exist, including the most effective dose, method of preparation and route of administration. Concerns also exist about the safety of using donor samples. With the publication of one controlled trial, and two additional trials in process, more data may help address these concerns. Additional pediatric data are especially needed.
References:
Gough E. Clin Infect Dis. 2011;53:994-1002.
Guo B. Aliment Pharmacol Ther. 2012;35:865-875.
Kassam Z. Am J Gastroenterol. 2013;108:500-508.
Russell G. Pediatrics. 2010;123:e239-e242.
Schutze GE. Pediatrics. 2013;131:196-200.
Surawicz CM. Am J Gastroenterol. 2013;108:478-498.
van Nood E. N Engl J Med. 2013;368:407-415.
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Disclosure: Bell serves on the speakers’ bureau for Sanofi-Pasteur (Sklice) and MedImmune (FluMist Quad).