Clostridioides difficile Infection in Children: Recent Updates on Epidemiology, Diagnosis, Therapy

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 diagnosis.^4,12,13  CDI is classified as healthcare-associated (onset more than 3 days after hospitalization) or community-associated (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-associated (Fig 1).¹²  Diversion of public health resources during 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 approach.¹⁵  Regardless, high rates of CDI in children are reported 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 evaluated for diarrhea in Perth, Australia.^16,17 

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 remains as high as 22% in toddlers 1 to 2 years of age before declining to approach rates seen in healthy adults of 1% to 3%.¹¹  This finding is consistent even among resource-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 incidence varies by country.²² 

For reasons unknown, infants appear almost universally protected from clinical disease despite these high colonization rates, even in the presence of toxin producing strains. Only rare cases of CDI in infants are reported,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 humans is required to substantiate this observation.²⁴  Although 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 pediatric populations are predisposed to higher rates of colonization, including those with inflammatory bowel disease, cystic fibrosis, and cancer as well as transplant recipients.^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 subsequent infection as CDI is more common in children with chronic medical conditions. For example, nearly all clinical isolates from pediatric oncology patients diagnosed with CDI during hospitalization were identical to their baseline admission isolates by pulsed-field gel electrophoresis 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 

Antibiotic exposure is the most important predisposing factor to the development of CDI.^32–34  Diarrhea in general 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 contributing. Antibiotics may specifically predispose to CDI through disruptions in intestinal microbial composition and metabolism, a state frequently referred to as dysbiosis. Through complex interactions, the distorted microbial 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 produce fermentable amino acids, such as leucine and ornithine, 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 infected with C. difficile.^32,33 

Given that CDI is mostly community-associated in children, 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 of C. difficile occurs fecal-orally through ingestion of spores, including by contact with contaminated surfaces in the environment. Whole genome sequencing indicates 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 children 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 exposure.^18,39,40  Potential transmission from companion animals has also been implicated.⁴¹ 

Ribotyping, a molecular technique often used for surveillance 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 previously the most common.¹²  In 2018, ribotype 106 accounted 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 

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 leukocytosis (≥15, 000 cells/mm³) or renal impairment (serum creatinine >1.5 mg/dL) in adults, is poorly defined in children, necessitating clinical judgement to diagnose. Severe complications of CDI in children include development of pseudomembranous colitis, pneumatosis intestinalis, 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 mortality 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 thickening, colonic dilation or free air in the case of perforation (Fig 2).

Recurrent CDI (rCDI) is as common in children as adults, occurring in about 20% to 30% of cases despite treatment.^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 proliferation of C. difficile, leading to relapse or reinfection.⁴⁸  Risk factors for recurrence include the presence of comorbidities such as cancer, IBD, medical technology dependence, 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) because of rCDI at one institution were found to have an alternative diagnosis, such as constipation or overflow diarrhea or inflammatory bowel disease, emphasizing the need for careful consideration of alternative causes of recurrent loose stools when faced with this dilemma.⁵⁰ 

The diagnosis of CDI in children is challenging, and detection does not always equate to diagnosis. There are several commercial tests available for diagnosis that either 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 colonization from infection. Tests that detect toxin, such as enzyme immunoassays, are more specific but lack sufficient 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. difficile demonstrated that toxin detection did not differ when compared with a cohort of children with symptomatic CDI.⁵²  Hence, correct interpretation of C. difficile test results ultimately requires careful consideration of patient 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 stewardship can further improve the predictive value of testing. First, diarrheal stool should preferentially only be collected from patients with unexplained and new-onset diarrhea, defined as 3 or more unformed stools within a 24 hour period.¹¹  An exception to this would be in patients with ileus or toxic megacolon suspected to be secondary 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 reaction was twice as common in asymptomatic children (28%) as in those presenting with acute gastroenteritis (14%), exemplifying the worth of incorporating age stratification 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-performing 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 developed 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 Gastroenterologists developed guidelines for the preferred management of CDI in adults, which are similar but differ slightly to the 2017 IDSA and SHEA guidelines by recommending use of testing algorithms that include a highly sensitive and a highly specific testing modality to distinguish colonization from active infection.⁵⁵  Despite societal guidance, testing practices for diagnosis of C. difficile in children varies considerably, suggesting further opportunities to improve diagnosis exist. Judicious testing of C. difficile ranks among one of the top 12 high-priority research topics in healthcare-associated infections and antimicrobial stewardship by the CDC.^56,57  Incorporation of clinical decision support around test ordering in electronic 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 polymerase chain reaction panels that include C. difficile targets may unintentionally increase inappropriate testing, so some laboratories 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.

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 

For symptomatic children, initial management should include discontinuation of the inciting antibiotic, when possible, to limit further intestinal microbial disruption. Current antimicrobial 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 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, however postguideline shifts in prescribing practice with decreased 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 metronidazole (71.1%) by day 5, whereas recurrence was similar.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 randomized to receive either oral fidaxomicin or vancomycin for 10 days. Children had to have negative rotavirus testing results 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 fidaxomcin (68%) compared with vancomycin (50%), with an adjusted treatment difference of 18.8% (95% confidence interval 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 Administration (FDA) expanded approval of fidaxomicin for treatment 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 vancomycin, which can be administered via gastric feeding tube in intubated children. Intravenous metronidazole is often 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 complications, such as hypotension, shock, ileus, or toxic megacolon arise, multiple interventions are instituted simultaneously in hopes of improving outcomes. When ileus is present, administration of vancomycin via retention enema can be attempted. Surgical intervention, in the form of either organ-preserving diverting loop ileostomy or more invasive colectomy 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 unknown. In practice, some prolong the course of CDI treatment, though relapse rates were similar in adults who received extended CDI therapy beyond 14 days in retrospective review, and further studies are still needed.^74,75  Prolonged use of metronidazole, which can be associated with neurotoxicity, should be avoided.

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 vancomycin regimens or vancomycin course followed by rifaximin chaser can be prescribed for second or subsequent recurrences after that. Secondary prophylaxis with oral vancomycin 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 currently 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 capsules 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, absence of a feeding tube, and lower number of recurrences of CDI before FMT. Just over 5% experienced an adverse reaction related to FMT, including diarrhea, pain, and bloating. There were 2 severe adverse events deemed related to FMT reported, including an aspiration pneumonia event post procedure and admission for emesis or diarrhea from inflammatory bowel disease relapse in another.⁷⁹ 

Despite these overall encouraging results, long term unanticipated consequences of FMT in children remain unknown. Changes in the microbiome have been implicated to contribute to autoimmune, metabolic, and psychiatric diseases, 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 coronavirus 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 children help to address screening and treatment but challenges around standardization and preparation of stool persist.⁸⁶  FMT is considered investigational, hence regulations around administration apply.⁸⁷ 

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 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 limitations 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 being 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 systemic effect and provision of enduring protection. Promising therapies that can provide direct neutralizing activity using amoeba, yeast, or bacteria vehicles are under very early stages of exploration.

Prevention of CDI is an important goal to protect children 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 spores and prevention of factors that promote progression to disease in those with established colonization.

In healthcare settings, attention to infection control practices 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 screening asymptomatic children on admission may decrease hospital 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 Infectious 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 estimated 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 antibiotics, the benefit of which is still debated. A large systematic review reported the risk of CDI was lowered 60% with probiotics. Conversely, in a recent trial of hospitalized 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 diarrhea was found.¹⁰⁶  The wide heterogeneity in formulations, dose, and optimal timing casts uncertainty on the generalizability of probiotics for CDI prevention. The 2017 IDSA and SHEA guidelines state there is insufficient evidence at this time to recommend use for primary prevention of CDI¹¹  Probiotics are generally well tolerated, though caution with use in severely immunocompromised or debilitated patients is needed and the cost to families must also be factored if used.¹⁰⁷ 

Other novel preventative approaches aimed at promoting colonization resistance by binding concomitantly administered antibiotics, such as activated charcoal and the oral β-lactamase ribaxamase, are under exploration.^108,109  Demonstration of protection against disease by antibodies to toxin supports ongoing efforts to develop a vaccine, but both toxin based and nontoxin based candidates are much further away from use in children.¹¹⁰ 

Recent progress made in our understanding of the epidemiology, 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 remain. Prioritizing translational research needs (Table 5) will allow us to make further advances to improve the outcomes of children affected by CDI.

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