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nhiễm Clostridioides difficile ở trẻ em
nhiễm Clostridioides difficile ở trẻ em
nhiễm Clostridioides difficile ở trẻ em
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
2 SHIRLEY et al
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of newborn rabbits, however further corroboration in hu- Given that CDI is mostly community-associated in chil-
mans is required to substantiate this observation.24 Al- dren, recent attention has focused on identifying specific
though protection from passive transplacental transfer of risk factors for this setting. In a large case-control study
maternal antibody is also unlikely the explanation based conducted by the Kaiser-Permanente system, risk factors
on maternal cord blood sampling, colonization may be for community-associated CDI in children included non-
important for acquired protection later in life, as natural Hispanic ethnicity, antibiotic exposure to amoxicillin-
immunization against toxin A and B does seem to occur clavulanate, cephalosporins or clindamycin within the
following colonization, irrespective of feeding method, previous 12 weeks, a previous positive C. difficile test
though the durability of this protection is unknown.25 within 6 months, and increased health care visits within
Beyond infancy and toddlerhood, other specific pediat- the last year.4 However, traditional risk factors may not
ric populations are predisposed to higher rates of coloni- always be present and 13.6% of children lacked any
zation, including those with inflammatory bowel disease, identifiable risk factor in another multisite case-control
cystic fibrosis, and cancer as well as transplant recipi- study of younger children with community-associated
ents.26–30 Up to one-quarter of hospitalized children may CDI.34
be asymptomatically colonized31 and one-third or more Transmission
of pediatric oncology patients may have asymptomatic C.
Transmission of C. difficile occurs fecal-orally through inges-
difficile colonization on admission. In these older age
tion of spores, including by contact with contaminated
groups, colonization serves as a risk factor for subse-
surfaces in the environment. Whole genome sequencing in-
quent infection as CDI is more common in children with
dicates that transmission of C. difficile among symptomatic
chronic medical conditions. For example, nearly all clini-
children within healthcare settings may be less common
cal isolates from pediatric oncology patients diagnosed
than in adult populations. Only about 12% of healthcare-
with CDI during hospitalization were identical to their
associated transmission events could be linked to another
baseline admission isolates by pulsed-field gel electro- symptomatic patient at a medical center that implemented
phoresis analysis; the caveat here being that diarrhea in contact isolation for all patients with diarrhea.38 Many chil-
children with cancer can be multifactorial, and it may not dren with healthcare associated CDI are already colonized
always be possible to clinically distinguish the primary with C. difficile at the time of admission.18 Infants, young
etiology.18 children, and household contacts with active CDI may serve
Risk Factors as possible sources of community-associated C. difficile ex-
posure.18,39,40 Potential transmission from companion ani-
Antibiotic exposure is the most important predisposing mals has also been implicated.41
factor to the development of CDI.32–34 Diarrhea in gen-
eral is a common side effect of antibiotics, occurring in Molecular Epidemiology
more than one third of patients who receive them, with Ribotyping, a molecular technique often used for surveil-
mechanisms such as osmotic effect and promotility con- lance purposes, characterizes C. difficile strains based on
tributing. Antibiotics may specifically predispose to CDI specific differences in ribosomal RNA. C. difficile ribotype
through disruptions in intestinal microbial composition 106 has emerged as the most common strain in the
and metabolism, a state frequently referred to as dysbio- United States, superseding the hypervirulent ribotype
sis. Through complex interactions, the distorted micro- 027 strain (also known as BI/NAP1), which was previ-
bial gut community can selectively promote survival of C. ously the most common.12 In 2018, ribotype 106 ac-
difficile.35 For example, enterococci are highly abundant counted for about 16% of community-associated and
in the stools of children with CDI. Enterococci may pro- 12% of healthcare-associated infections in the United
duce fermentable amino acids, such as leucine and orni- States.12 Ribotype 106 is also the most common strain in
thine, whereas depleting arginine, leading to metabolic the pediatric population.42 Globally, ribotype 014 (ST2,
alterations in the gut that may further promote CDI.36 ST13, ST49/clade 1) appears to be common.43
Any antibiotic class can potentially predispose to CDI and
onset can occur within days to weeks of exposure. In CLINICAL
particular, third generation cephalosporins, clindamycin, C. difficile causes a wide spectrum of disease severity,
fluoroquinolones, and amoxicillin-clavulanate are strong ranging from asymptomatic carriage all the way to life
associations.33,37 Several other factors that predispose to threatening colitis. Diarrhea is thought to primarily result
CDI are described, including administration of proton from toxin-mediated intestinal epithelial cytotoxicity and
pump inhibitors, tube feeds, healthcare facility exposure, inflammation. Most symptomatic children will have mild-
prolonged hospitalization, and contact with a person in- to-moderate diarrhea. Severe CDI, defined by leukocyto-
fected with C. difficile.32,33 sis ($15, 000 cells/mm3) or renal impairment (serum
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.
4 SHIRLEY et al
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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- institutions to improve appropriate test ordering.58 Gaining
ification in testing approach.53 Third, prolonged carriage in popularity, the use of multiplex gastrointestinal polymer-
can occur despite treatment, so repeat testing for proof ase chain reaction panels that include C. difficile targets may
of test of cure is not helpful.54 unintentionally increase inappropriate testing, so some labo-
The recommended diagnostic approach has evolved ratories preferentially suppress C. difficile results from the
with time from toxin-based assays to NAAT-based testing panel unless specifically requested, as another way to limit
and currently to multistep testing. As the best-perform- over testing in populations with low prevalence of CDI.59
ing approach for diagnosis, the 2017 IDSA and SHEA The search for novel stool biomarkers to improve diagnosis
guidelines recommend using a stool toxin test as part of is an ongoing and pressing need. Measurement of fecal
a 2-step algorithm (Fig 3), unless institutions have devel- metabolites,60 proinflammatory cytokines,61 and volatile
oped other agreed upon clinical and laboratory criteria organic compounds62 all hold promise as potential future
for test submission, in which case detection of toxigenic makers.
C. difficile by NAAT alone is considered acceptable.11
More recently in 2021, the American College of Gastroen- MANAGEMENT
terologists developed guidelines for the preferred man- The management of CDI is determined by the number
agement of CDI in adults, which are similar but differ and severity of episodes. Children who do not respond to
slightly to the 2017 IDSA and SHEA guidelines by recom- targeted treatment within 5 days should be re-evaluated
mending use of testing algorithms that include a highly for other causes. There is currently insufficient evidence
sensitive and a highly specific testing modality to distin- to support probiotics as an alternative to antimicrobial
guish colonization from active infection.55 Despite socie- therapy for CDI treatment.63
tal guidance, testing practices for diagnosis of C. difficile
in children varies considerably, suggesting further oppor- First Episode
tunities to improve diagnosis exist. Judicious testing of C. For symptomatic children, initial management should include
difficile ranks among one of the top 12 high-priority re- discontinuation of the inciting antibiotic, when possible, to
search topics in healthcare-associated infections and anti- limit further intestinal microbial disruption. Current antimi-
microbial stewardship by the CDC.56,57 Incorporation of crobial therapies targeted against the initial CDI episode of
clinical decision support around test ordering in elec- mild or moderate severity include oral metronidazole and
tronic health records and preauthorization of testing are oral vancomycin (Table 2). Metronidazole, which has been a
additional strategies successfully implemented by some mainstay treatment of pediatric CDI, was removed as a
recommended first line choice for adults in the 2017 IDSA 10 days. Children had to have negative rotavirus testing re-
and SHEA guidelines.11 Vancomycin and fidaxomicin are sults to be eligible, and children with inflammatory bowel
now recommended as preferred first line therapies in adults disease were excluded.70 No difference in clinical response at
based on improved clinical cure rates and lower recurrence the end of therapy was shown, however at 30 days after
risk.11,64–67 High quality data to support treatment guideline therapy, the rate of sustained response was higher with fi-
recommendation in children were lacking at the time, how- daxomcin (68%) compared with vancomycin (50%), with an
ever postguideline shifts in prescribing practice with de- adjusted treatment difference of 18.8% (95% confidence in-
creased use of metronidazole and increased use of oral terval 1.5%–35.3%). Children under 2 years of age were
vancomycin in children with CDI have been observed.7,68 included, so it is unclear if other etiologies contributed to
A retrospective, comparative effectiveness study of 192 diarrhea in younger participants.71 Regardless, based on
children hospitalized with nonsevere CDI has since shown these positive results, in 2020 the US Food and Drug Admin-
that those treated with vancomycin had earlier resolution of istration (FDA) expanded approval of fidaxomicin for treat-
symptoms (86.3%) compared with those treated with metro- ment of CDI to include children 6 months of age and older.
nidazole (71.1%) by day 5, whereas recurrence was simi- These 2 studies open up new therapeutic options in children.
lar.69 The recent landmark SUNSHINE study represents the Based on limited data extrapolated from care in adults,
first clinical trial conducted in children with CDI. In this phase children with more severe disease are treated with oral van-
3 trial, 142 children with CDI were age-stratified and ran- comycin, which can be administered via gastric feeding tube
domized to receive either oral fidaxomicin or vancomycin for in intubated children. Intravenous metronidazole is often
6 SHIRLEY et al
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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 oral vancomycin in children (Table 2). Pulse-tapered vanco-
of metronidazole are adequate in this situation. There are no mycin regimens or vancomycin course followed by rifaximin
optimal treatments for fulminant disease. When complica- chaser can be prescribed for second or subsequent recur-
tions, such as hypotension, shock, ileus, or toxic megacolon rences after that. Secondary prophylaxis with oral vancomy-
arise, multiple interventions are instituted simultaneously in cin while receiving systemic antibiotics may reduce the risk
hopes of improving outcomes. When ileus is present, admin- of recurrent CDI in the highest risk pediatric patients with an
istration of vancomycin via retention enema can be at- established history of CDI.76,77 Bezlotoxumab, an antitoxin B
tempted. Surgical intervention, in the form of either organ- monoclonal antibody providing modest risk reduction, is cur-
preserving diverting loop ileostomy or more invasive colec- rently recommended in adults at high risk of recurrence.64,78
tomy or FMT are other deliberations.11,72,73 Further studies Results of the phase 3 trial in children are expected soon.
are needed to improve outcomes from severe disease. FMT, which involves transfer of stool from a healthy
The optimal management of children who require donor to the gastrointestinal tract of a recipient with
treatment with other concomitant antibiotics beyond the rCDI has gained popularity as a potential way to restore
recommended duration of CDI targeted therapy is un- disrupted intestinal microbial composition. Traditionally,
known. In practice, some prolong the course of CDI treat- donor stool is transferred via endoscopy or enteric cap-
ment, though relapse rates were similar in adults who sules for treatment, but enema may be an option if the
received extended CDI therapy beyond 14 days in retro- other methods are unavailable. In a large retrospective
spective review, and further studies are still needed.74,75 review of FMT in 335 patients performed at 18 pediatric
Prolonged use of metronidazole, which can be associated centers between 2014 and 2017, 81% of children were
with neurotoxicity, should be avoided. successfully treated, increasing to 87% with repeat FMT.
Predictors of successful outcome included use of fresh
Recurrent CDI donor stool over frozen stool, delivery by endoscopy, ab-
For the first recurrence, the 2017 IDSA and SHEA guidelines sence of a feeding tube, and lower number of recurrences
recommend retreatment can be with oral metronidazole or of CDI before FMT. Just over 5% experienced an adverse
reaction related to FMT, including diarrhea, pain, and live purified Firmicutes bacterial spores from healthy donors.
bloating. There were 2 severe adverse events deemed re- In a trial of adults at risk for rCDI, lower recurrence rates at
lated to FMT reported, including an aspiration pneumo- 8 weeks after treatment were found compared with placebo.89
nia event post procedure and admission for emesis or These developments represent important steps forward toward
diarrhea from inflammatory bowel disease relapse in standardization of FMT, although they are several more steps
another.79 further away from potentially being available options for use in
Despite these overall encouraging results, long term un- children. Ridinilazole, a novel narrow spectrum antimicrobial;90
anticipated consequences of FMT in children remain un- ibezapolstat, a DNA polymerase inhibitor;91 and MGB-BP-3, a
known. Changes in the microbiome have been implicated to novel topoisomerase inhibitor, are other C. difficile therapeutics
contribute to autoimmune, metabolic, and psychiatric dis- advancing through later stages of clinical development.92
eases, hence any treatment that involves alterations in the All currently available C. difficile therapies have limita-
microbiome at such an early age warrants further long- tions to use (Table 3). Even established therapies such as
term investigation.80–82 The FDA has also issued several vancomycin and metronidazole can increase the risk of
safety alerts regarding potential transmission of multidrug recurrence, disrupt the gut microbiota, induce resistance,
resistant organisms, severe acute respiratory syndrome co- and promote proliferation of multidrug resistant bacteria,
ronavirus 2 virus and Mpox virus by FMT, highlighting the while none of the upcoming treatments are currently be-
risk of transmission of emerging transmissible pathogens ing studied in children as of yet.93–99 Characteristics of
posed by FMT.82–85 Published societal guidelines for chil- an ideal C. difficile therapy include a safe and effective
dren help to address screening and treatment but chal-
agent that can be administered directly to the gut with
lenges around standardization and preparation of stool
minimal influence on local microbial composition or sys-
persist.86 FMT is considered investigational, hence regula-
temic effect and provision of enduring protection. Promis-
tions around administration apply.87
ing therapies that can provide direct neutralizing activity
Upcoming Treatments using amoeba, yeast, or bacteria vehicles are under very
early stages of exploration.
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 PREVENTION
diarrhea within 8 weeks was shown by clinical trial when Prevention of CDI is an important goal to protect chil-
compared with placebo, leading to FDA approval for adults dren and limit healthcare costs. In the absence of a safe
in December 2022.88 Following closely behind in development and effective vaccine, prevention strategies rely on a 2-
is SER-109, an oral microbiome biotherapeutic composed of pronged approach of prevention of spread of C. difficile
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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
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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