Clostridioides difficile Infection in

Children: Recent Updates on

Epidemiology, Diagnosis, Therapy
Debbie-Ann Shirley, MD, MPH,a William Tornel,a Cirle A. Warren, MD,b,c Shannon Moonah, MD, ScMb

Clostridioides (formerly Clostridium) difficile is the most important infectious abstract

cause of antibiotic-associated diarrhea worldwide and a leading cause of
healthcare-associated infection in the United States. The incidence of C. difficile
infection (CDI) in children has increased, with 20 000 cases now reported
annually, also posing indirect educational and economic consequences. In
contrast to infection in adults, CDI in children is more commonly community-
associated, accounting for three-quarters of all cases. A wide spectrum of
disease severity ranging from asymptomatic carriage to severe diarrhea can
occur, varying by age. Fulminant disease, although rare in children, is associ-
ated with high morbidity and even fatality. Diagnosis of CDI can be challenging
as currently available tests detect either the presence of organism or disease- a
Pediatric Infectious Diseases, Department of Pediatrics,
causing toxin but cannot distinguish colonization from infection. Since coloni- b
Infectious Diseases and International Health, Department
of Medicine, and cComplicated C. difficile Clinic, UVA Health,
zation can be high in specific pediatric groups, such as infants and young
University of Virginia, Charlottesville, Virginia
children, biomarkers to aid in accurate diagnosis are urgently needed. Similar
Drs Shirley and Moonah conceptualized the review,
to disease in adults, recurrence of CDI in children is common, affecting 20% to drafted the manuscript, and reviewed and revised the
manuscript; Mr Tornel contributed to the design and
30% of incident cases. Metronidazole has long been considered the mainstay helped to draft the manuscript; Dr Warren critically
therapy for CDI in children. However, new evidence supports the safety and ef- reviewed the manuscript for important intellectual
content; and all authors approved the final manuscript
ficacy of oral vancomycin and fidaxomicin as additional treatment options, as submitted and agree to be accountable for all
whereas fecal microbiota transplantation is gaining popularity for recurrent in- aspects of the work.

fection. Recent advancements in our understanding of emerging epidemiologic DOI: https://doi.org/10.1542/peds.2023-062307

trends and management of CDI unique to children are highlighted in this re- Accepted for publication May 31, 2023

view. Despite encouraging therapeutic advancements, there remains a pressing Address correspondence to Debbie-Ann Shirley, MD, MPH,
Department of Pediatrics, PO Box 800386, Charlottesville,
need to optimize CDI therapy in children, particularly as it pertains to severe VA 22908. E-mail: ds3ru@virginia.edu
and recurrent disease. PEDIATRICS (ISSN Numbers: Print, 0031-4005; Online,
1098-4275).
This is an open access article distributed under the terms of
Clostridioides (formerly Clostridium) difficile is a spore-forming, anaerobic, the Creative Commons Attribution-NonCommercial-
NoDerivatives 4.0 International License (http://
Gram-positive bacillus first described in 1935 from the stool of healthy new- creativecommons.org/licenses/by-nc-nd/4.0/), which permits
born infants.1 Initially named Bacillus difficile, because it was difficult to isolate, noncommercial, distribution, and reproduction in any me-
dium, provided the original author and source are credited.
with time this pathogen has also proven difficult to treat and control. Most
FUNDING: This work was supported by the Hartwell
C. difficile bacteria secrete toxin A and toxin B. The presence of toxin B appears Foundation and the NIH, R01 DK131313 and R34
to be the primary cause of diarrhea, and sufficient by itself to induce disease, AI165304. The Hartwell Foundation and the NIH had no
role in the design and conduct of the study.
whereas other virulence factors, such as binary toxin, surface layer protein, and
CONFLICT OF INTEREST DISCLOSURES: Dr Warren is a
biofilm formation, may contribute to colonization, transmission, or disease medical advisor for SER-109. The rest of the authors
severity. have indicated they have no conflicts of interest
relevant to this article to disclose.
C. difficile has risen to become a leading cause of healthcare-associated infec-
tion among adult populations in the United States, resulting in an estimated
half-million attributable cases each year, leading to 223 900 people requiring To cite: Shirley D-A, Tornel W, Warren CA, et al.
hospital care and 12 800 deaths.2,3 CDI prolongs hospital stay and increases Clostridioides difficile Infection in Children: Recent
Updates on Epidemiology, Diagnosis, Therapy.
healthcare expenses, costing the US healthcare system at least 1 billion dollars Pediatrics. 2023;152(3):e2023062307
annually.3 The US Centers for Disease Control and Prevention (CDC) have

PEDIATRICS Volume 152, number 3, September 2023:e2023062307 STATE-OF-THE-ART REVIEW

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 identified C. difficile as an urgent threat, listing it as one
of the top 5 drug-resistant pathogens in need of aggres-
sive action.3
Although CDI is more common and tends to be more
severe in older adults, the burden of C. difficile to chil-
dren is also significant (Fig 1). C. difficile is the most im-
portant infectious cause of antibiotic-associated diarrhea
in children, contributing approximately 20 000 infections
in the United States each year.4,5 Rates of CDI in children
have increased over the past 3 decades and the rate of
pediatric hospitalizations resulting from or complicated
by C. difficile increased 57% from 1997 to 2006.5,6 There
is some more recent indication of leveling rates, particu-
larly in the inpatient setting.2,7,8 Changes in testing, diag-
nosis, treatment and strain type can all contribute to
fluctuations in incidence. Nonetheless, CDI-associated hospi-
talizations cost 1.6 times more than non-CDI associated
hospitalizations in children, and CDI adds an additional
4 days to length of stay for pediatric hospitalizations.9
Broader, less well-described indirect consequences of CDI on
child health also bear consideration, including educational
consequences from lost days of schooling and economic
impact from missed parental days of work.10
The Infectious Diseases Society of America (IDSA) and
the Society for Healthcare Epidemiology of America
(SHEA) updated CDI clinical practice guidelines in 2017,
including, for the first time, specific recommendations re-
garding CDI diagnosis and therapeutic considerations in
children.11 Our understanding of CDI in children has con-
tinued to grow since the release of these guidelines. This
review summarizes recent updates pertaining to the ep-
idemiology, diagnosis, and management of CDI in chil-
dren, with a principle focus on developments over the
past 5 years.
FIGURE 1
The impact of Clostridioides difficile infection in children.
2 SHIRLEY et al
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EPIDEMIOLOGY
Incidence and Prevalence
The incidence of CDI as a cause of diarrhea in children has
increased over time, though the exact magnitude of this
problem is challenging to quantify given limitations in diag-
nosis.4,12,13 CDI is classified as healthcare-associated (onset
more than 3 days after hospitalization) or community-asso-
ciated (onset within 3 days of hospitalization provided no
documented overnight stay in a healthcare facility in the
preceding 12 weeks). CDI, considered mostly a healthcare-
associated infection in adults, contrasts as most commonly
community-associated in children, nonetheless community-
associated CDI rates have increased in both adults and
children.2,4 Population-based surveillance conducted by the
CDC Emerging Infections Program estimates the incidence
of community-associated CDI in children was as high as
25.8 per 100 000 in 2019, accounting for 75% of cases,
compared with 9.0 per 100 000 reported as healthcare-as-
sociated (Fig 1).12 Diversion of public health resources dur-
ing the coronavirus disease 2019 pandemic has since led to
delays in subsequent surveillance estimates.14
The global impact of CDI in children is even harder to
quantify given even wider variations in diagnostic ap-
proach.15 Regardless, high rates of CDI in children are re-
ported worldwide. A recent cross-sectional study conducted
among children presenting with acute gastroenteritis at a
tertiary children’s hospital in Zhejiang, China, for example,
reported 14.3% of cases solely attributed to CDI.16 Whereas,
C. difficile was detected from 19.7% of children being evalu-
ated for diarrhea in Perth, Australia.16,17
Age
The prevalence of detection of C. difficile in the stools of
children varies by age. Infants have high frequencies of
asymptomatic carriage, exceeding 40% within the first
year.18 Colonization, which begins shortly after birth,
peaks at 6 to 12 months of age.19–21 The frequency re-
mains as high as 22% in toddlers 1 to 2 years of age be-
fore declining to approach rates seen in healthy adults of
1% to 3%.11 This finding is consistent even among re-
source-limited settings, where detection of C. difficile is
also prevalent during the first year of life, then declining
during the second year of life, though cumulative inci-
dence varies by country.22
For reasons unknown, infants appear almost univer-
sally protected from clinical disease despite these high
colonization rates, even in the presence of toxin produc-
ing strains. Only rare cases of CDI in infants are repor-
ted,23 but other age-related causes such as necrotizing
enterocolitis may still be at play. A popularly purported
reason that infants do not develop diarrhea from CDI is
the lack of expression of receptors for binding C. difficile
toxins, based on limited animal data from the intestines
 of newborn rabbits, however further corroboration in hu-
mans is required to substantiate this observation.24 Al-
though protection from passive transplacental transfer of
maternal antibody is also unlikely the explanation based
on maternal cord blood sampling, colonization may be
important for acquired protection later in life, as natural
immunization against toxin A and B does seem to occur
following colonization, irrespective of feeding method,
though the durability of this protection is unknown.25
Beyond infancy and toddlerhood, other specific pediat-
ric populations are predisposed to higher rates of coloni-
zation, including those with inflammatory bowel disease,
cystic fibrosis, and cancer as well as transplant recipi-
ents.26–30 Up to one-quarter of hospitalized children may
be asymptomatically colonized31 and one-third or more
of pediatric oncology patients may have asymptomatic C.
difficile colonization on admission. In these older age
groups, colonization serves as a risk factor for subse-
quent infection as CDI is more common in children with
chronic medical conditions. For example, nearly all clini-
cal isolates from pediatric oncology patients diagnosed
with CDI during hospitalization were identical to their
baseline admission isolates by pulsed-field gel electro-
phoresis analysis; the caveat here being that diarrhea in
children with cancer can be multifactorial, and it may not
always be possible to clinically distinguish the primary
etiology.18
Risk Factors
Antibiotic exposure is the most important predisposing
factor to the development of CDI.32–34 Diarrhea in gen-
eral is a common side effect of antibiotics, occurring in
more than one third of patients who receive them, with
mechanisms such as osmotic effect and promotility con-
tributing. Antibiotics may specifically predispose to CDI
through disruptions in intestinal microbial composition
and metabolism, a state frequently referred to as dysbio-
sis. Through complex interactions, the distorted micro-
bial gut community can selectively promote survival of C.
difficile.35 For example, enterococci are highly abundant
in the stools of children with CDI. Enterococci may pro-
duce fermentable amino acids, such as leucine and orni-
thine, whereas depleting arginine, leading to metabolic
alterations in the gut that may further promote CDI.36
Any antibiotic class can potentially predispose to CDI and
onset can occur within days to weeks of exposure. In
particular, third generation cephalosporins, clindamycin,
fluoroquinolones, and amoxicillin-clavulanate are strong
associations.33,37 Several other factors that predispose to
CDI are described, including administration of proton
pump inhibitors, tube feeds, healthcare facility exposure,
prolonged hospitalization, and contact with a person in-
fected with C. difficile.32,33
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Given that CDI is mostly community-associated in chil-
dren, recent attention has focused on identifying specific
risk factors for this setting. In a large case-control study
conducted by the Kaiser-Permanente system, risk factors
for community-associated CDI in children included non-
Hispanic ethnicity, antibiotic exposure to amoxicillin-
clavulanate, cephalosporins or clindamycin within the
previous 12 weeks, a previous positive C. difficile test
within 6 months, and increased health care visits within
the last year.4 However, traditional risk factors may not
always be present and 13.6% of children lacked any
identifiable risk factor in another multisite case-control
study of younger children with community-associated
CDI.34
Transmission
Transmission of C. difficile occurs fecal-orally through inges-
tion of spores, including by contact with contaminated
surfaces in the environment. Whole genome sequencing in-
dicates that transmission of C. difficile among symptomatic
children within healthcare settings may be less common
than in adult populations. Only about 12% of healthcare-
associated transmission events could be linked to another
symptomatic patient at a medical center that implemented
contact isolation for all patients with diarrhea.38 Many chil-
dren with healthcare associated CDI are already colonized
with C. difficile at the time of admission.18 Infants, young
children, and household contacts with active CDI may serve
as possible sources of community-associated C. difficile ex-
posure.18,39,40 Potential transmission from companion ani-
mals has also been implicated.41
Molecular Epidemiology
Ribotyping, a molecular technique often used for surveil-
lance purposes, characterizes C. difficile strains based on
specific differences in ribosomal RNA. C. difficile ribotype
106 has emerged as the most common strain in the
United States, superseding the hypervirulent ribotype
027 strain (also known as BI/NAP1), which was previ-
ously the most common.12 In 2018, ribotype 106 ac-
counted for about 16% of community-associated and
12% of healthcare-associated infections in the United
States.12 Ribotype 106 is also the most common strain in
the pediatric population.42 Globally, ribotype 014 (ST2,
ST13, ST49/clade 1) appears to be common.43
CLINICAL
C. difficile causes a wide spectrum of disease severity,
ranging from asymptomatic carriage all the way to life
threatening colitis. Diarrhea is thought to primarily result
from toxin-mediated intestinal epithelial cytotoxicity and
inflammation. Most symptomatic children will have mild-
to-moderate diarrhea. Severe CDI, defined by leukocyto-
sis ($15, 000 cells/mm3) or renal impairment (serum
3
 creatinine >1.5 mg/dL) in adults, is poorly defined in
children, necessitating clinical judgement to diagnose.
Severe complications of CDI in children include develop-
ment of pseudomembranous colitis, pneumatosis intesti-
nalis, toxic megacolon, perforation, peritonitis, and shock
with multisystem failure.44 Severe CDI is less common in
children than adults, but does occur, and up to 8% of
will develop severe disease.45 By other estimates, up to
0.1% to 1.2% may require colectomy, and all-cause mor-
tality in children with CDI is about 2% to 4%.7 Imaging
and endoscopic findings of CDI are nonspecific. Disease
in children is often cecocolonic or colonic. In severe
cases, abdominal imaging may show colonic wall thicken-
ing, colonic dilation or free air in the case of perforation
(Fig 2).
RECURRENT CDI
Recurrent CDI (rCDI) is as common in children as adults,
occurring in about 20% to 30% of cases despite treat-
ment.11,46,47 Recurrence is defined as new onset of CDI
symptoms with a positive C. difficile specific laboratory
test following an incident episode in the previous 2 to 8
weeks. Ongoing dysbiosis perpetuates survival and prolif-
eration of C. difficile, leading to relapse or reinfection.48
Risk factors for recurrence include the presence of co-
morbidities such as cancer, IBD, medical technology de-
pendence, recent surgery, and antibiotic exposure.49 The
risk of additional recurrent episodes increase with each
recurrence. Interestingly, nearly one-fourth of children
referred for fecal microbiota transplantation (FMT) be-
cause of rCDI at one institution were found to have an al-
ternative diagnosis, such as constipation or overflow
diarrhea or inflammatory bowel disease, emphasizing the
need for careful consideration of alternative causes of re-
current loose stools when faced with this dilemma.50
LABORATORY DIAGNOSIS
The diagnosis of CDI in children is challenging, and de-
tection does not always equate to diagnosis. There are
FIGURE 2
Severe Clostridioides difficile infection in children. (A) Abdominal radiograph showing thickened colon most prominent in the transverse co-
lon. (B) Abdominal sonogram showing hypoechoic diffuse large bowel wall thickening. (C) CT Abdomen and pelvis showing markedly thick-
ened colon wall in an adolescent with fulminant C. difficile colitis.
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several commercial tests available for diagnosis that ei-
ther detect the presence of C. difficile organism or toxin
production, but each has limitations in application and
there is no gold standard (Table 1). Tests that detect
the organism, such as nucleic acid amplification tests
(NAATs), are highly sensitive but do not distinguish colo-
nization from infection. Tests that detect toxin, such as
enzyme immunoassays, are more specific but lack suffi-
cient sensitivity for diagnosis. Detection of toxin does not
correlate with severity of symptoms in children nor can
stool toxin concentration reliably distinguish carriage
from infection.51 A prospective study of asymptomatic
children with cancer, cystic fibrosis, or inflammatory
bowel disease in which 21% were colonized with C. diffi-
cile demonstrated that toxin detection did not differ
when compared with a cohort of children with symptom-
atic CDI.52 Hence, correct interpretation of C. difficile test
results ultimately requires careful consideration of pa-
tient factors. Consequences of misinterpretation include
unnecessary antibiotic exposure, potential drug adverse
effects, and delay in diagnosis of the true cause of
diarrhea.
Adherence to several strategies of diagnostic steward-
ship can further improve the predictive value of testing.
First, diarrheal stool should preferentially only be col-
lected from patients with unexplained and new-onset di-
arrhea, defined as 3 or more unformed stools within a
24 hour period.11 An exception to this would be in pa-
tients with ileus or toxic megacolon suspected to be sec-
ondary to severe CDI. Second, testing should be avoided
when a more likely cause of diarrhea, such as laxative
use, is apparent. Following similar reasoning, other more
likely causes should be evaluated before testing children
under 2 years of age, and testing should generally be
avoided in infants less than 1 year of age, given the high
rates of asymptomatic colonization in these young age
groups. In a multicenter investigation of children under 2
years of age, C. difficile detection by polymerase chain re-
action was twice as common in asymptomatic children
(28%) as in those presenting with acute gastroenteritis
 TABLE 1 Summary of Clostridioides difficile Testinga
Test Target Strengths Limitations
Tests to detect presence of C. difficile organism
GDH EIA Detects C. difficile-specific enzyme
High sensitivity;
Low specificitya;

rapid, takes hours to complete;
does not distinguish toxigenic

inexpensive from nontoxigenic strains
NAATs Detects genes for C. difficile toxin
High sensitivity;
Lower positive predictive value;
(toxin A/B)
good specificity;
does not detect presence of

can be rapid toxin
Toxigenic culture Detects toxin producing C. difficile
High sensitivity;
Technically complex to perform;
strains
high specificity;
takes days to complete;

allows for antimicrobial
used mostly as reference for
susceptibility testing validation or in research
settings
Tests to detect presence of C. difficile toxin
Toxin EIA Detects free toxin in stool (toxin A/B)
High specificity;
Low sensitivity (variable but as

rapid, takes hours to complete; low as 35%)111

inexpensive
CCNA Demonstrates free toxin B
High sensitivity;
Technically complex to perform;

high specificity
takes day to complete;

used mostly as reference for
validation or in research
settings
a
The 2017 IDSA and SHEA guideline recommends a 2-step algorithm (ie, glutamate dehydrogenase EIA plus toxin EIA, arbitrated by NAAT or NAAT plus toxin EIA) as the best diag-
nostic approach.11
CCNA, cell culture cytotoxicity neutralization assay; EIA, enzyme immunoassay; GDH, Glutamate dehydrogenase; NAATs, nucleic acid amplification tests.

(14%), exemplifying the worth of incorporating age strat-
ification in testing approach.53 Third, prolonged carriage
can occur despite treatment, so repeat testing for proof
of test of cure is not helpful.54
The recommended diagnostic approach has evolved
with time from toxin-based assays to NAAT-based testing
and currently to multistep testing. As the best-perform-
ing approach for diagnosis, the 2017 IDSA and SHEA
guidelines recommend using a stool toxin test as part of
a 2-step algorithm (Fig 3), unless institutions have devel-
oped other agreed upon clinical and laboratory criteria
for test submission, in which case detection of toxigenic
C. difficile by NAAT alone is considered acceptable.11
More recently in 2021, the American College of Gastroen-
terologists developed guidelines for the preferred man-
agement of CDI in adults, which are similar but differ
slightly to the 2017 IDSA and SHEA guidelines by recom-
mending use of testing algorithms that include a highly
sensitive and a highly specific testing modality to distin-
guish colonization from active infection.55 Despite socie-
tal guidance, testing practices for diagnosis of C. difficile
in children varies considerably, suggesting further oppor-
tunities to improve diagnosis exist. Judicious testing of C.
difficile ranks among one of the top 12 high-priority re-
search topics in healthcare-associated infections and anti-
microbial stewardship by the CDC.56,57 Incorporation of
clinical decision support around test ordering in elec-
tronic health records and preauthorization of testing are
additional strategies successfully implemented by some
institutions to improve appropriate test ordering.58 Gaining
in popularity, the use of multiplex gastrointestinal polymer-
ase chain reaction panels that include C. difficile targets may
unintentionally increase inappropriate testing, so some labo-
ratories preferentially suppress C. difficile results from the
panel unless specifically requested, as another way to limit
over testing in populations with low prevalence of CDI.59
The search for novel stool biomarkers to improve diagnosis
is an ongoing and pressing need. Measurement of fecal
metabolites,60 proinflammatory cytokines,61 and volatile
organic compounds62 all hold promise as potential future
makers.
MANAGEMENT
The management of CDI is determined by the number
and severity of episodes. Children who do not respond to
targeted treatment within 5 days should be re-evaluated
for other causes. There is currently insufficient evidence
to support probiotics as an alternative to antimicrobial
therapy for CDI treatment.63
First Episode
For symptomatic children, initial management should include
discontinuation of the inciting antibiotic, when possible, to
limit further intestinal microbial disruption. Current antimi-
crobial therapies targeted against the initial CDI episode of
mild or moderate severity include oral metronidazole and
oral vancomycin (Table 2). Metronidazole, which has been a
mainstay treatment of pediatric CDI, was removed as a

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 FIGURE 3
A laboratory testing approach for diagnosis of Clostridioides difficile infection in children.a
a
Based on the 2017 IDSA and SHEA guideline, which recommends a 2-step algorithm, including s stool toxin test (ie, glutamate dehydroge-
nase EIA plus Toxin EIA, arbitrated by NAAT or NAAT plus toxin EIA) as the best diagnostic approach.11 Discordant results require further clin-
ical evaluation. c/w, consistent with; CDI, Clostridioides difficile infection; EIA, enzyme immunoassay; GDH, glutamate dehydrogenase; ID,
Infectious Disease; NAAT, nucleic acid amplification test; Toxin A/B, Toxin A and B enzyme immunoassay; yo, years old.

recommended first line choice for adults in the 2017 IDSA
and SHEA guidelines.11 Vancomycin and fidaxomicin are
now recommended as preferred first line therapies in adults
based on improved clinical cure rates and lower recurrence
risk.11,64–67 High quality data to support treatment guideline
recommendation in children were lacking at the time, how-
ever postguideline shifts in prescribing practice with de-
creased use of metronidazole and increased use of oral
vancomycin in children with CDI have been observed.7,68
A retrospective, comparative effectiveness study of 192
children hospitalized with nonsevere CDI has since shown
that those treated with vancomycin had earlier resolution of
symptoms (86.3%) compared with those treated with metro-
nidazole (71.1%) by day 5, whereas recurrence was simi-
lar.69 The recent landmark SUNSHINE study represents the
first clinical trial conducted in children with CDI. In this phase
3 trial, 142 children with CDI were age-stratified and ran-
domized to receive either oral fidaxomicin or vancomycin for
10 days. Children had to have negative rotavirus testing re-
sults to be eligible, and children with inflammatory bowel
disease were excluded.70 No difference in clinical response at
the end of therapy was shown, however at 30 days after
therapy, the rate of sustained response was higher with fi-
daxomcin (68%) compared with vancomycin (50%), with an
adjusted treatment difference of 18.8% (95% confidence in-
terval 1.5%–35.3%). Children under 2 years of age were
included, so it is unclear if other etiologies contributed to
diarrhea in younger participants.71 Regardless, based on
these positive results, in 2020 the US Food and Drug Admin-
istration (FDA) expanded approval of fidaxomicin for treat-
ment of CDI to include children 6 months of age and older.
These 2 studies open up new therapeutic options in children.
Based on limited data extrapolated from care in adults,
children with more severe disease are treated with oral van-
comycin, which can be administered via gastric feeding tube
in intubated children. Intravenous metronidazole is often

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 TABLE 2 Summary of Therapies for Children With Clostridioides difficile Infection^
Presentation Drug# Route Dose Frequency Duration
Initial infection
Nonsevere Metronidazole* or PO 7.5 mg/kg per dose TID or QID 10 d
(max 500 mg)
Vancomycin PO 10 mg/kg per dose QID 10 d
(max 125 mg)
Severea or fulminant Vancomycin PO or PR 10 mg/kg per dose QID 10 d
(max 500 mgb)
± Metronidazole IV 10 mg/kg per dose TID 10 d
(max 500 mg)
Recurrent infection
First recurrence Metronidazole* or PO 7.5 mg/kg per dose TID or QID 10 d
(max 500 mg)
Vancomycin PO 10 mg/kg per dose QID 10 d
(max 125 mg)
Second or Vancomycin or PO 10 mg/kg per dose QID 10 d (if not used previously)
subsequent (max 125 mg)
recurrencec Vancomycin tapered PO 10 mg/kg per dose QID 10–14 d, then BID x 7 d, then once daily × 7
and pulsed or (max 125 mg) d, then every 2–3 d for 2–8 wk
Vancomycin; followed PO 10 mg/kg per dose QID; TID 10 d; 20 d
by rifaximin chaser (max 125 mg); no
or pediatric dosing for
rifaximin0 (max 400 mg)
FMT under IND — — — —
^
Data based on the 2017 IDSA and SHEA guidelines.11 *Some experts would preferentially administer vancomycin over metronidazole for initial treatment or recurrence based
on accumulating data to suggest vancomycin may be more effective. # Fidaxomicin is a newly US FDA approved option for treatment in children, weight based dosing 16 mg/kg
per dose (max 200 mg per dose) BID x 10 d, available as tablet and liquid formulations for children $6 mo of age and $4 kg.111 'Rifaximin is not US FDA approved for use in
children <12 y of age. 1/– consider addition of. BID, twice daily; FDA, Food and Drug Administration; d, days; IV, intravenous; mg, milligrams; PO, by mouth; PR, per rectum; QID,
4 times daily; TID, 3 times daily.
a
No validated definition of severity in children, based on clinical judgment.
b
Consider serum trough levels when using higher dosing levels to prevent systemic toxicity.
c
Consider fecal microbiota transplantation under investigational use for patients with multiple recurrences following standard antibiotic treatments.

added on, though it is unclear whether colonic concentrations
of metronidazole are adequate in this situation. There are no
optimal treatments for fulminant disease. When complica-
tions, such as hypotension, shock, ileus, or toxic megacolon
arise, multiple interventions are instituted simultaneously in
hopes of improving outcomes. When ileus is present, admin-
istration of vancomycin via retention enema can be at-
tempted. Surgical intervention, in the form of either organ-
preserving diverting loop ileostomy or more invasive colec-
tomy or FMT are other deliberations.11,72,73 Further studies
are needed to improve outcomes from severe disease.
The optimal management of children who require
treatment with other concomitant antibiotics beyond the
recommended duration of CDI targeted therapy is un-
known. In practice, some prolong the course of CDI treat-
ment, though relapse rates were similar in adults who
received extended CDI therapy beyond 14 days in retro-
spective review, and further studies are still needed.74,75
Prolonged use of metronidazole, which can be associated
with neurotoxicity, should be avoided.
Recurrent CDI
For the first recurrence, the 2017 IDSA and SHEA guidelines
recommend retreatment can be with oral metronidazole or
oral vancomycin in children (Table 2). Pulse-tapered vanco-
mycin regimens or vancomycin course followed by rifaximin
chaser can be prescribed for second or subsequent recur-
rences after that. Secondary prophylaxis with oral vancomy-
cin while receiving systemic antibiotics may reduce the risk
of recurrent CDI in the highest risk pediatric patients with an
established history of CDI.76,77 Bezlotoxumab, an antitoxin B
monoclonal antibody providing modest risk reduction, is cur-
rently recommended in adults at high risk of recurrence.64,78
Results of the phase 3 trial in children are expected soon.
FMT, which involves transfer of stool from a healthy
donor to the gastrointestinal tract of a recipient with
rCDI has gained popularity as a potential way to restore
disrupted intestinal microbial composition. Traditionally,
donor stool is transferred via endoscopy or enteric cap-
sules for treatment, but enema may be an option if the
other methods are unavailable. In a large retrospective
review of FMT in 335 patients performed at 18 pediatric
centers between 2014 and 2017, 81% of children were
successfully treated, increasing to 87% with repeat FMT.
Predictors of successful outcome included use of fresh
donor stool over frozen stool, delivery by endoscopy, ab-
sence of a feeding tube, and lower number of recurrences
of CDI before FMT. Just over 5% experienced an adverse

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 TABLE 3 Strengths and Limitations of Current C. difficile Therapies in Children
Therapeutic Strengths
Metronidazole
Established experience
Vancomycin
Established experience;

not systemically absorbed
Fidaxomicin
Narrow spectrum gut activity;

not systemically absorbed
Bezlotoxumab
No systemic activity;

no affect on gut dysbiosis
Fecal microbiota transplantation
May help to restore gut microbial dysbiosis
reaction related to FMT, including diarrhea, pain, and
bloating. There were 2 severe adverse events deemed re-
lated to FMT reported, including an aspiration pneumo-
nia event post procedure and admission for emesis or
diarrhea from inflammatory bowel disease relapse in
another.79
Despite these overall encouraging results, long term un-
anticipated consequences of FMT in children remain un-
known. Changes in the microbiome have been implicated to
contribute to autoimmune, metabolic, and psychiatric dis-
eases, hence any treatment that involves alterations in the
microbiome at such an early age warrants further long-
term investigation.80–82 The FDA has also issued several
safety alerts regarding potential transmission of multidrug
resistant organisms, severe acute respiratory syndrome co-
ronavirus 2 virus and Mpox virus by FMT, highlighting the
risk of transmission of emerging transmissible pathogens
posed by FMT.82–85 Published societal guidelines for chil-
dren help to address screening and treatment but chal-
lenges around standardization and preparation of stool
persist.86 FMT is considered investigational, hence regula-
tions around administration apply.87
Upcoming Treatments
Rebyota (RBX2660) is an FMT product administered rectally
as a single dose of commercially prepared stool from healthy
screened donors. Higher treatment success with absence of
diarrhea within 8 weeks was shown by clinical trial when
compared with placebo, leading to FDA approval for adults
in December 2022.88 Following closely behind in development
is SER-109, an oral microbiome biotherapeutic composed of
8 SHIRLEY et al
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Limitations

Broad spectrum gut microbial activity with
recurrence risk;

systemically absorbed;

neurotoxic with prolonged or repeated use

Broad spectrum gut microbial activity with
recurrence risk;

promotes resistant pathogens such as
vancomycin resistant enterococci

Limited experience with use in children;

expensive;

adverse effects of pyrexia, abdominal pain,
emesis, diarrhea, constipation, elevation in
liver enzyme activity and rash reported

Insufficient data in children;

caution in those with congestive heart failure;

short-lived protection

Difficult to standardize;

no long term safety data on consequences of
altering child microbiome yet available;

risk of transmission of donor derived
infections or conditions
live purified Firmicutes bacterial spores from healthy donors.
In a trial of adults at risk for rCDI, lower recurrence rates at
8 weeks after treatment were found compared with placebo.89
These developments represent important steps forward toward
standardization of FMT, although they are several more steps
further away from potentially being available options for use in
children. Ridinilazole, a novel narrow spectrum antimicrobial;90
ibezapolstat, a DNA polymerase inhibitor;91 and MGB-BP-3, a
novel topoisomerase inhibitor, are other C. difficile therapeutics
advancing through later stages of clinical development.92
All currently available C. difficile therapies have limita-
tions to use (Table 3). Even established therapies such as
vancomycin and metronidazole can increase the risk of
recurrence, disrupt the gut microbiota, induce resistance,
and promote proliferation of multidrug resistant bacteria,
while none of the upcoming treatments are currently be-
ing studied in children as of yet.93–99 Characteristics of
an ideal C. difficile therapy include a safe and effective
agent that can be administered directly to the gut with
minimal influence on local microbial composition or sys-
temic effect and provision of enduring protection. Promis-
ing therapies that can provide direct neutralizing activity
using amoeba, yeast, or bacteria vehicles are under very
early stages of exploration.
PREVENTION
Prevention of CDI is an important goal to protect chil-
dren and limit healthcare costs. In the absence of a safe
and effective vaccine, prevention strategies rely on a 2-
pronged approach of prevention of spread of C. difficile
 TABLE 4 Key Points of C. difficile Infection in Children
Key Points

Clostridioides difficile infection (CDI) is an important cause of antibiotic-associated diarrhea and healthcare-associated infection in children.

A multistep approach is currently recommended for diagnosis

Newer treatment options for CDI in children include oral vancomycin and fidaxomicin

Recurrence of CDI is common and presents a therapeutic challenge; fecal microbiome transplantation, an exploratory therapy to restore distorted
microbial communities, is becoming more commonly used in children

More child focused investigation is warranted to improve the burden of CDI in children

spores and prevention of factors that promote progres- Prevention of Disease

sion to disease in those with established colonization.
Prevention of Transmission
In healthcare settings, attention to infection control practi-
ces and facility cleaning may help to limit the spread of
C. difficile. As alcohol-based hand sanitizers do not inactivate
spores, exercising meticulous hand hygiene with soap and
water after caring for a patient with CDI is recommended.11
Contact isolation includes the donning of gloves and gowns
by healthcare workers, with dedicated use of private patient
rooms when available. Gloves have been shown to reduce
the risk of hand contamination when caring for patients
with CDI.100 Computer-simulated modeling suggests screen-
ing asymptomatic children on admission may decrease hos-
pital onset CDI by 28.5%, but incorporating universal
screening as part of a multi-intervention bundle could prove
logistically prohibitive for some institutions given the high
rates of colonization in some pediatric populations coupled
with pediatric bed shortages.101
As spores remain hardy in the environment surviving
months or longer, environmental cleaning with approved
sporicidal disinfectants is advised, as staying in a hospital
room previously occupied by a patient with CDI increases
risk of the current occupant.102 Ultraviolet disinfection has
become a widely used and promising adjunctive measure.103
The American Academy of Pediatrics Committee on Infec-
tious diseases advises that children with CDI be excluded
from child care settings until stools are contained within the
diaper or the child is continent and stool frequency is no
more than 2 stools above normal frequency.104
Exposure to antibiotics is the most important modifiable
risk factor for development of CDI. Antibiotic stewardship
programs that target reduction of inappropriate use in
adults have proven helpful in reducing CDI rates, though
comparable data in children are needed.105 Stewardship
efforts are also needed in the outpatient setting, with at
least 30% of outpatient antibiotic prescriptions esti-
mated to be unnecessary.7 Probiotics have been used as
a preventative measure for C. difficile in an attempt to
restore some of the microbial disruption caused by anti-
biotics, the benefit of which is still debated. A large sys-
tematic review reported the risk of CDI was lowered
60% with probiotics. Conversely, in a recent trial of hos-
pitalized children who received antibiotics randomized
to receive Lactobacillus reuteri (2 × 108 CFU) or placebo
twice daily for the duration of antibiotic treatment, no
difference in prevention of antibiotic associated diar-
rhea was found.106 The wide heterogeneity in formula-
tions, dose, and optimal timing casts uncertainty on the
generalizability of probiotics for CDI prevention. The
2017 IDSA and SHEA guidelines state there is insuffi-
cient evidence at this time to recommend use for pri-
mary prevention of CDI11 Probiotics are generally well
tolerated, though caution with use in severely immuno-
compromised or debilitated patients is needed and the
cost to families must also be factored if used.107
Other novel preventative approaches aimed at pro-
moting colonization resistance by binding concomitantly
administered antibiotics, such as activated charcoal and
the oral b-lactamase ribaxamase, are under explora-
tion.108,109 Demonstration of protection against disease

TABLE 5 Research priorities for improving outcomes in children with C. difficile infection
Diagnosis Development of diagnostic biomarkers to improve the performance of currently available testing strategies in order to more
accurately differentiate infection from colonization
Therapy Development of C. difficile targeted therapies that:

can be delivered locally to the gut and with limited systemic effects

have narrow spectrum activity to limit intestinal dysbiosis

maintain long lasting effect to decrease recurrence and

are also effective for treatment of severe disease
Prevention Development of safe and effective C. difficile vaccines or other preventative measures that promote resistance to C. difficile
colonization

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 by antibodies to toxin supports ongoing efforts to de-
velop a vaccine, but both toxin based and nontoxin
based candidates are much further away from use in
children.110
CONCLUSIONS
Recent progress made in our understanding of the epidemi-
ology, risk, and management of CDI in children allows us to
improve upon pediatric considerations in the diagnosis and
treatment of this common infection (Table 4). Much of our
current practice is still adapted from generalizing findings
from adult studies, however significant knowledge gaps re-
main. Prioritizing translational research needs (Table 5) will
allow us to make further advances to improve the outcomes
of children affected by CDI.
ABBREVIATIONS
CDC: Centers for Disease Control and Prevention
CDI: Clostridioides difficile infection
FDA: Food and Drug Administration
FMT: fecal microbiota transplantation
NAAT: nucleic acid amplification
rCDI: recurrent Clostridioides difficile infection
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