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carriage of toxigenic C. difficile in infants<12 months of age. When C. difficile or its toxins are detected in the stool of an infant, clinicians may not be able to determine with certainty that a positive result represents CDI.
∙ Clinicians should test NICU patients for CDI only if there is evidence of pseudomembranous colitis or if the patient has clinically significant diarrhea and other noninfectious and infectious causes of diarrhea have been excluded.
In general, a case of CDI is defined as the presence of clinically
significant diarrhea or toxic megacolon in conjunction with either a positive test for toxigenic C. difficile or its toxins in the stool, or evidence of pseudomembranous colitis by endoscopy, surgery, or histopathology. For adults, the IDSA/SHEA clinical practice guideline for C. difficile infection recommends patients with unex- plained and new-onset ≥3 unformed stools in 24 hours as the preferred target population for testing for CDI.5 Testing patients without clinically significant diarrhea will decrease the positive predictive value of a positive test for CDI,6 but no universally accepted or validated definition of clinically significant diarrhea exists for infants. In addition, infants<12 months of age have a high rate of colonization with C. difficile,7–9 and even when diarrhea is present, it is difficult to be certain that a positive test result represents CDI (as opposed to the detection of colonization in a patient in whom theremay be alternative etiologies of diarrhea). For these reasons, and because of the lack of a clear association between positive tests and true clinical disease in infants, the IDSA/SHEA guideline recommends that testing for CDI should never be routi- nely recommended in endemic circumstances for neonates or infants<12 months of age who have diarrhea.5 Question: Before or concurrent with C. difficile testing, which gastrointestinal pathogens should clinicians test for in a NICU patient who develops diarrhea? Answer: Before testing a NICU patient with suspected infectious diarrhea for CDI, clinicians should
∙ Perform a thorough investigation for potential noninfec- tious causes of diarrhea in NICU patients.
∙ Test the stool for norovirus, rotavirus, adenovirus, and enterovirus.
∙ Consider bacterial stool cultures (eg, Salmonella, Shigella, Campylobacter, Yersinia,and Shiga-toxin–producing E. coli) for infants who were admitted to the NICU from the community, or who have a known or suspected exposure to bacterial enteritis.
and toxigenic strains can persist for months.3,8,10 In the absence of a clear association with infant disease, the authors do not advise testing for CDI unless other possibilities have been excluded.11 Because diarrhea in a NICU patient is often noninfectious,
Approximately 35% of neonates are colonized with C. difficile,
before testing for CDI, clinicians should perform a thorough examination and review of the infant’s medical history, feeding, and medications to exclude other more likely causes of diarrhea (eg, feeding intolerance or milk protein allergy, malabsorption, opioid withdrawal, etc). Cohort studies evaluating the prevalence of viruses in the stool of
NICU patients have shown low endemic rates of gastrointestinal pathogens.12 Norovirus, rotavirus, enteroviruses, and adenoviruses are common pathogens and have been reported to cause infections and outbreaks in preterm infants.13–17 Therefore, the authors sug- gest testing for these viruses in an infant with suspected infectious
Thomas J. Sandora et al
diarrhea if providers have access to a laboratory with those cap- abilities. The presence of C. difficile toxin can create cytopathic effects in tissue culture and can lead to false-positive results for stool viral culture.18 Because C. difficile toxin would be expected to be present due to colonization in a substantial proportion of infants, the authors suggest that facilities use polymerase chain reaction (PCR) assays (a sensitive and rapid testing method for these viruses) as a preferredmodality for viral testing. An outbreak may warrant a broader investigation of potential pathogens. Bacterial pathogens such as Salmonella19 and Escherichia coli20–22
have been linked to NICU outbreaks. Routinely testing NICU patients with suspected infectious diarrhea for bacterial pathogens is unlikely to have a high yield, but in the setting of a community or hospital outbreak, symptomatic family or healthcare contacts, recent admission from the community, or concern for bloody or muco- purulent diarrhea, such testing
maybewarranted.Someinstitutions use multiplex PCR assays to identify gastrointestinal pathogens, and some of these panels include C. difficile. If a multiplex panel is used to test a NICU patient for other pathogens, clinicians should be aware that C. difficile may be detected with high frequency in this age group. A positive result may reflect colonization rather than infec- tion and may not warrant treatment.23 For this reason, some facil- ities suppress the C. difficile result on these panels and require a separate dedicated test if CDI is a concern. Question: What are the best methods for testing for CDI in NICU patients? Answer:
∙ If clinicians consider testing a NICU patient for CDI, the authors advise using a stool toxin test as part of a multistep algorithm rather than using a nucleic acid amplification test (NAAT) alone.
∙ The facility should not use toxin enzyme immunoassay (EIA) as a stand-alone test to diagnose CDI.
∙ Repeat testing after a negative result and tests of cure are not recommended.
Because CDI is a toxin-mediated disease, any testing strategy must include detection of either toxin or a toxigenic organism.
1. NAATs, primarily polymerase chain reaction testing for the genes for toxins A and B,
∙ Are more sensitive for C. difficile detection than toxin EIA tests, but
∙ Their positive predictive value can be low,24 particu- larly when the prevalence of colonization is high (as is true for infants).
2. Toxin EIA testing
∙ In addition to having lower sensitivity than NAAT, may also be prone to false-positive results in children.25
∙ Is not recommended as a stand-alone approach to diagnosis.
3. Glutamate dehydrogenase (GDH) immunoassays
∙ Detect a highly conserved antigen present in all C. difficile isolates.
∙ Can be used as a component of 2- or 3-step algorithms with subsequent toxin testing, in which a negative toxin EIA result is sometimes arbitrated by NAAT as outlined in the IDSA/SHEA guideline.5
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