Testing

The diagnosis of pediatric CDI is made by stool tests. Major associations recommend enzyme immunoassay (EIA) for glutamate dehydrogenase (GDH) as a screening tool because of its near 100% sensitivity.8 Glutamate dehydrogenase is an antigen that is present in CDI.1 Positive GDH screenings only indicate presence of C difficile, regardless of toxigenic or nontoxigenic strain.1,8

An initial GDH screening is typically performed in conjunction with a nucleic acid amplification test (NAAT), often through polymerase chain reaction (PCR), to detect the genes responsible for the production of toxins A and B.1,2,7 Although NAAT has been recognized as the most sensitive method for detection of C difficile, a first-line standard testing method has not been established.3

The American Academy of Pediatrics (AAP) states that the testing of children younger than age 1 year is not routinely recommended in children with diarrhea unless the patient has known risk factors, such as gut motility disorders or Hirschsprung disease, or if the patient is in the setting of a C difficile outbreak.3 Children between the ages of 1 and 2 years should not be tested unless other viral etiologies have been investigated and ruled out. Pediatric patients older than age 2 years should be tested in patients with prolonged or worsening diarrhea.3,16


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Testing for alternative or concomitant enteropathogens should also be considered, including stool culture of other organisms and ova and parasite testing.1 A multistep approach for screening and confirmatory testing seems to be the best strategy for diagnosis.1,2,4 Biomarkers such as fecal calprotectin can also be ordered: an increase of this neutrophil product can be used as a marker for intestinal inflammation and may be useful in deciphering colonization vs true infection. Fecal leukocytes may also be present in stools.8

Abdominal radiographs or noncontrast abdominal computed tomography (CT) scans may be ordered for severe or fulminant disease to rule out colonic dilation,19 wall thickening, or perforation.2,7 Although colonoscopy with biopsy is extremely sensitive, this invasive imaging modality is only considered in atypical presentations.20

Treatment

The initial step in management of pediatric CDI is prompt cessation of the inciting antibiotic therapy.2,7,16 In very mild disease, discontinuation of antibiotics may be sufficient to reverse the disease process without use of medications.2 The continuation of antibiotic therapy puts the patient at increased risk for recurrent infection.7 If antibiotic therapy cannot be terminated because of concomitant infection, switch to an antibiotic with the narrowest spectrum.2

Empiric antibiotic therapy against C difficile should be commenced if the results of testing are delayed for greater than 48 hours or if the patient is showing signs of severe or fulminant infection.2,7 If not, it is recommended that positive laboratory results be obtained before treatment is initiated.2 Symptomatic support with aggressive intravenous (IV) fluid resuscitation is crucial in children with diarrhea.1 Antimotility drugs, such as loperamide, are discouraged because of associated poor outcomes, such as toxic megacolon or ileus, but are considered safe to use once antibiotic treatment against CDI has been initiated.2,11

Antibiotic treatment for pediatric CDI depends on the severity of illness and whether it is the first episode or a recurrence of infection (Table 2).8,21 In the 2017 updated Infectious Diseases Society of America guidelines, the severity of illness is defined as nonsevere (previously mild/moderate), severe, and fulminant (previously complicated).8 For children with nonsevere CDI, the recommended antibiotics are metronidazole and vancomycin for 10 days.8,21 In nonsevere cases of CDI, clinical improvement with antibiotic therapy should occur within 1 to 2 days of initiation, but about 31% of pediatric cases need a second course of antibiotics.1,11

For children with severe CDI, the guidelines recommend oral vancomycin over metronidazole whereas for fulminant CDI, the guidelines recommend vancomycin for 10 days (oral or rectal) with or without metronidazole IV for 10 days.8,21

Metronidazole is the preferred initial treatment for nonsevere pediatric CDI because of its affordability and efficacy against vancomycin-resistant enterococcus (VRE).8 Metronidazole is typically administered orally 3 times a day for 10 days. It is secreted across the intestinal mucosa, causing it to achieve high fecal concentrations. This medication is associated with more frequent AEs than vancomycin, such as nausea, vomiting, metallic taste, and abdominal cramps. Serious complications, such as encephalopathy or peripheral neuropathy, are uncommon but are still possible with metronidazole.2,7 Metronidazole is typically avoided for recurrent episodes as repeat exposure may lead to neurotoxicity.2,12 Vancomycin is not absorbed in the GI tract, causing it to achieve high fecal concentrations and, in turn, producing higher rates of recovery.16 Notable AEs of vancomycin include abdominal pain, nausea, and hypokalemia.7

Fidaxomicin is a new macrolide that was approved for use in pediatric CDI patients aged 6 months and older in February 2020.22 Fidaxomicin has minimal systemic absorption, leading to high concentrations in the colon, and may have other benefits compared with vancomycin. The SUNSHINE study was a multicenter, randomized, blinded clinical trial that enrolled pediatric patients from 39 sites to evaluate the efficacy of vancomycin and fidaxomicin in pediatric CDI. Although both treatments are effective for pediatric CDI, study results showed evidence of higher clinical response and cure and lower recurrence with the use of fidaxomicin compared with vancomycin.23 Fidaxomicin has been shown to cause less new-onset colonization of Candida and vancomycin-resistant enterococcus (VRE) species.24 Despite promising results thus far, more studies are necessary to evaluate fidaxomicin and its efficacy in recurrent pediatric CDI.

Rifaximin is an oral rifamycin derivative antibiotic that is being evaluated as an alternative initial treatment for CDI because of its favorable side effect profile.25 Rifaximin has been shown to stimulate the growth of Lactobacillus in the gut and does not significantly alter the gut flora.26 In a small, randomized, controlled trial comparing the efficacy of metronidazole with rifaximin in patients aged 12 to 18 years with IBD and nonsevere CDI, there was no statistically significant difference in the results.25 This could indicate that rifaximin could be a viable alternative for pediatric patients with CDI and coexisting IBD. Further studies are needed to provide evidence of the efficacy of rifaximin and ability to decrease recurrence rates and to gain FDA approval for use of this medication for pediatric CDI.

Recurrent Clostridioides difficile Infection

Approximately 22% of children with an initial episode of CDI will have a recurrence.27 The guidelines for treatment for a nonsevere first recurrence is metronidazole for 10 days or vancomycin for 10 days. For a second or subsequent recurrence, vancomycin is given in a tapered and pulsed regimen or for 10 days followed by rifaximin for 20 days or fecal microbiota transplantation (FMT).8

Fecal Microbiota Transplantation

Fecal microbiota transplantation should be considered as a treatment option for pediatric patients with 3 or more recurrences for whom antibiotic therapy is not successful.6,8,28 Fecal microbiota transplantation is the administration of fecal content and gut organisms from a healthy donor’s GI tract into a patient with recurrent CDI via a nasogastric tube, colonoscopy, or enema.2,12 For patient with CDI, FMT through oral capsules is the preferred method of fecal administration.2,7 The goal of FMT is to restore the GI tract into a healthy balanced microbiome to discourage C difficile colonization and generate an immunologic response that promotes eradication of C difficile.2

Limited data exist regarding FMT in pediatric patients, with much of that available information consisting of individual case studies.29 A few studies on FMT in pediatric CDI do show promising results, supporting the consideration of FMT as a treatment strategy for pediatric CDI. In a retrospective study that included 335 pediatric patients with CDI (age range, 11-23 years), 81% had a successful outcome after a single FMT and 86.6% had a successful outcome after a first or repeated FMT.30 Additional data is required to evaluate the efficacy and safety of FMT to support the use of this treatment in recurrent pediatric CDI. The 2019 safety alert for use of FMT in adults cannot be ignored and, as biotherapeutics are explored as a possible alternative to this treatment in adults, the use of FMT in children should also be further assessed for safety and efficacy.31