Clostridioides difficile in children

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Biology, epidemiology, and risk factors

Clostridioides difficile is a spore-forming, gram-positive, anaerobic organism that is ubiquitous in the environment. Person-to-person transmission via the fecal–oral route is the primary mode of infection, facilitated by ingestion of spores that are highly resistant to disinfectants and can survive for prolonged periods outside the host ^[1]. The acid resistance of the spores allows them to pass readily through the stomach, enabling germination in the small bowel. In persons colonized with C difficile, disruption of the gut microbiome predisposes to overgrowth of the organism in the colonic environment ^[2][3]. Disease manifestations are primarily attributable to exotoxins A and B, which target and inactivate Rho- and Ras-GTPases, leading to cytoskeleton degradation, tight junction disruption, endothelial cell death, compromised colonic epithelial barrier, and increased colonic permeability ^[2][3].

Asymptomatic colonization is common in young children, particularly in those younger than 2 years of age ^[4]. In a recent systematic review and meta-analysis of 95 studies involving 19,186 children, the asymptomatic colonization rate for toxigenic or non-toxigenic C difficile was 15% (95% CI 7 to 25) during the first week of life, rising to 36% (95% CI 28 to 45) in infants 3 to 6 months of age, 41% (95% CI 32 to 50) in infants 6 to 12 months of age, then declined to 22% (95% CI 14 to 32) between 1 and 2 years of age, 17% (95% CI 12 to 23) between 2 and 5 years of age, and 12% (95% CI 7 to 18) in children 5 years of age or older ^[4]. Rates of asymptomatic colonization with toxigenic strains were also highest in those 3 months to 2 years of age (range 11% to 14%) ^[4]. For reasons that have not been fully elucidated, and despite these high colonization rates, infants and young children rarely develop symptoms. Potential explanations, though unproven, include lack of expression of receptors for C difficile toxin binding (based on newborn rabbit model) and presence of protective maternal antibodies ^[5][6].

C difficile infection (CDI) can be healthcare- or community-associated. Healthcare-associated CDI is defined by symptom onset more than 3 days after hospitalization, while community-associated CDI is defined by symptom onset before or within 3 days of admission with no history of hospitalization or any other healthcare exposure within the previous 12 weeks. Over the past 10 to 15 years, overall rates of CDI in both Canada and the United States have been declining ^[7]-[12]. Population-based surveillance in the U.S. for children and youth aged 1 to 17 years in 2022 showed a community-associated CDI incidence rate of 21 per 100,000 population and 8.1 per 100,000 for hospital-associated CDI ^[12]. Hospital-based surveillance in Canada between 2015 and 2020 demonstrated an overall decline in CDI incidence among children and youth 1 to 17 years of age; two-thirds of cases were healthcare-associated and one-third community-associated ^[10]. An important caveat to this study’s findings is that it predominantly captured data on hospitalized children and, therefore, may have underestimated community-associated CDI incidence.

Antibiotic exposure is the predominant risk factor for CDI. While any antibiotic can predispose to CDI, those most commonly implicated include amoxicillin-clavulanate, third-generation cephalosporins, carbapenems, quinolones, and clindamycin ^[13]-[15]. Factors that increase likelihood of C difficile acquisition include healthcare facility exposure, prolonged hospitalization, or contact with a person infected with C difficile. Conditions that increase risk of disease in those colonized include antibiotic exposure, proton pump inhibitor therapy, prolonged tube feeds, gastrointestinal tract surgery, or underlying medical conditions such as inflammatory bowel disease (IBD), renal insufficiency, or immune-compromising states ^[13][15].

Clinical presentation

The presence of toxin-producing C difficile in stool is associated with a wide spectrum of gastrointestinal manifestations, ranging from asymptomatic carriage to pseudomembranous colitis. The case definition for CDI in children includes the presence of symptoms (usually diarrhea), absence of an alternative cause for diarrhea, and either a stool result that is positive for C difficile toxin or colonoscopic findings indicative of pseudomembranous colitis (e.g., inflammation with elevated yellow and white coalescing colonic plaques) ^[16]. High rates of asymptomatic carriage in infants and young children lead to difficulties in diagnosing CDI in this age group.

Symptomatic illness may be mild-to-moderate (non-severe) or severe. While clinical judgment is required to assign severity and guide treatment, non-severe illness is usually characterized by watery diarrhea (6 or more episodes in 36-hour period), low-grade fever, and mild abdominal pain ^[1]. Severe disease is associated with symptoms and signs of systemic toxicity such as high-grade fever and rigors. Severe illness may be complicated by hypotension, shock, peritonitis, ileus, or megacolon. Pseudomembranous colitis is characterized by worsening diarrhea, abdominal pain, fever, leukocytosis, systemic toxicity, and stool containing blood, mucous, and leukocytes. The most critical manifestation of pseudomembranous colitis is toxic megacolon, which can lead to intestinal perforation. Severe or fatal disease is rare in children and youth. However, complications are more likely to occur among neutropenic individuals with hematological malignancies or those treated with hematopoietic stem-cell transplantation, infants with Hirschsprung’s disease, and children or youth with IBD.

Laboratory diagnosis

A number of tests are available for detection of C difficile or its toxins ^[5][17]. For detection of the organism, the two most common assays in current use are nucleic acid amplification tests (NAATs) and the glutamate dehydrogenase enzyme immunoassay (GDH EIA). The former detects presence of C difficile toxin A or B genes, while the latter detects presence of C difficile-specific enzymes. Both are highly sensitive but have limited specificity because they do not distinguish colonization from infection. Toxigenic culture can detect the presence of toxin-producing strains for C difficile and is highly sensitive and specific, but testing is technically complex to perform, time-consuming, and not available in most clinical laboratories. Tests that detect toxin in the stool include EIA assays and the cell culture cytotoxicity assay (CCNA). Toxin EIAs have high specificity but limited sensitivity. CCNA is highly sensitive and specific but technically complex to perform, time-consuming, and unavailable in clinical laboratories.

To optimize diagnostic accuracy, a two-step testing strategy is recommended by the Infectious Disease Society of America (IDSA) and the Society for Healthcare Epidemiology of America (SHEA)^[17]. Stool is first tested by either NAAT or GDH EIA. A negative result indicates that CDI is unlikely, and no further testing is performed. A sample that tests positive by NAAT or GDH EIA is reflexively tested by toxin EIA. If both the screen and toxin EIA are positive, CDI is likely. A screen test-positive and toxin EIA-negative result is considered indeterminate. In this circumstance, additional testing may be considered (e.g., if NAAT was the initial screen, then do GDH EIA [or vice versa] as a confirmatory test) though clinical judgment is needed in deciding whether treatment is warranted in such situations.

Diagnostic stewardship principles are important in deciding whether to test for C difficile ^[5]. Testing should generally be reserved for children with risk factors for CDI and three or more unformed stools per day or children with ileus or toxic megacolon when C difficile is considered a possible culprit. Testing should be discouraged when acute gastroenteritis due to typical viral and bacterial pathogens is suspected. In children younger than 2 years of age and, in particular, those younger than 1 year of age, testing should be discouraged given their high asymptomatic colonization rate and rarity of disease.

Treatment

The high frequency of C difficile and its toxins in the gastrointestinal tract of healthy infants and children confounds the diagnosis of CDI in a child experiencing watery (non-bloody) diarrhea with toxin present in the stool. In many cases, the illness resolves without specific treatment. Even if a decision is made to treat, clinicians should be aware of the possible presence of another pathogen. In all cases of antibiotic-associated diarrhea, the offending agent should be discontinued immediately, if possible. When antibiotic therapy cannot be stopped, an antibiotic less commonly associated with CDI or one from a different class may be considered, if feasible without compromising care.

For patients with non-severe CDI where treatment is deemed warranted (e.g., symptoms not resolving after discontinuing antibiotics) vancomycin or metronidazole are appropriate treatment options (Table 1)^[5][18][19]. Vancomycin as first-line therapy is supported by a recently published observational study (n=192) of children aged 2 to 17 years with non-severe CDI that demonstrated lower clinical resolution rates with metronidazole than vancomycin (OR 0.40; 95% CI, 0.17 to 0.97, p = 0.04), although relapse rates within 12 weeks of treatment were similar (OR 1.47; 95% CI, 0.58 to 3.75, p=0.42)^[20].

Vancomycin administered orally is recommended for severe uncomplicated CDI as well as for severe complicated CDI when oral administration is an option (Table 1) ^[5][18][19]. For complicated CDI where oral administration is not possible (e.g., ileus) vancomycin can be administered rectally. The addition of intravenous metronidazole should be considered for severe complicated disease. (Metronidazole can be given intravenously because enterohepatic circulation deposits some drug in the gut.) Vancomycin has no efficacy for CDI when administered intravenously. Colectomy may be required in intractable cases.

Relapses occur in 10% to 30% of children after stopping treatment. Risk factors for recurrence include re-exposure to antibiotics, immunocompromising conditions such as malignancy, inborn errors of immunity, secondary immune deficiency, or organ transplantation, and underlying chronic non-immunocompromising conditions ^[21]-[24]. In some studies, treatment of the initial episode with metronidazole versus vancomycin was associated with higher recurrence risk in children with underlying immunocompromising or other chronic medical conditions ^[21][23]. Relapses do not imply drug resistance and therefore, for children with non-severe CDI and no underlying medical conditions, retreatment with the same medication as for the first episode is appropriate. For children with non-severe CDI and underlying medical conditions, and particularly those with severe immunocompromising conditions in whom metronidazole was used for the first episode, vancomycin is preferred.

For the treatment of the second or later recurrence of CDI, a tapered regimen with oral vancomycin is recommended (Table 1). Another option that can be considered selectively, in consultation with an expert in the field, is oral fidaxomicin. In a recently published paediatric randomized trial of fidaxomicin versus vancomycin for CDI (n=148), fidaxomicin was associated with a higher rate of cure without recurrence (68.4% versus 50.0%, adjusted treatment difference 18.8%; 95% CI, 1.5% to 35.3%) ^[25]. Although paediatric data on extended pulsed fidaxomicin regimens are lacking, emerging adult data from a single randomized controlled trial suggest good efficacy and low recurrence rates ^[26]. Cost is an important limitation to the use of fidaxomicin.

The management of intractable cases and multiple recurrences is challenging and consultation with individuals experienced in managing these cases is advised. Fecal microbiota transplantation (FMT) is one potential treatment option for such cases. In a retrospective study involving 18 paediatric centres, 80.9% of 335 children (~8% were transplant /oncology patients) had no recurrence of CDI within 2 months of FMT ^[27]. Thirty-four of the 64 patients with recurrence were relapse-free at 2 months following a second FMT, leading to an overall success rate of 86.6% ^[27]. Adverse effects reported in the immediate aftermath of FMT include vomiting with dehydration and aspiration pneumonia ^[27]. Potential long-term adverse effects such as transmission of multidrug-resistant organisms and other pathogens, and alteration to the gut microbiome that could potentially contribute to autoimmune, metabolic, or psychiatric diseases may be of concern ^[5]. Emerging therapeutics related to FMT found to be effective in phase III clinical trials in adults (RBX2660, SER-109) are products that contain purified, well defined organism populations originally derived from healthy donors ^[28][29].

Secondary prophylaxis with oral vancomycin while receiving systemic antibiotic therapy may be warranted in certain patients with history of CDI and risk factors for recurrence. In one retrospective evaluation of 74 children, 30 of whom received secondary vancomycin prophylaxis, the risk of CDI recurrence was significantly lower in those who received secondary prophylaxis despite having more risk factors for recurrence (3% versus 25%, p=0.02) ^[30].

Prevention

A detailed review of infection prevention and control strategies is beyond the scope of this statement. Key strategies include but are not limited to:

• Meticulous hand hygiene. Washing hands with soap and water is the recommended hand hygiene method in the context of C difficile transmission prevention (alcohol-based hand hygiene products do not kill C difficile spores).
• Judicious use of antibiotics is an essential strategy to reduce CDI risk. Stewardship principles include accurate diagnosis, selection of narrow-spectrum, targeted antibiotic therapy, and optimizing antibiotic treatment duration. Within institutions, implementation of antimicrobial stewardship initiatives is a key step toward reducing CDI risk.
• Identifying and removing environmental sources of C difficile and using chlorine-containing or other sporicidal cleaning agents to eliminate environmental contamination in areas associated with increased rates or outbreaks of CDI.
• Contact precautions should be maintained until 48 hours after resolution of diarrhea.
• Use of private rooms or cohorting.
• Stool should not be retested once symptoms abate. The decision to isolate patients should be based on symptoms alone because stools often remain toxin-positive despite cure.

Recommendations

Diagnosis

• Clostridioides difficile (C difficile)-associated infection should be considered in children older than 2 years of age with otherwise unexplained diarrhea and antibiotic exposure within the previous 12 weeks or with other underlying risk factors.
• Testing for C difficile is not routinely recommended for healthy children under 2 years of age.
• Accurate diagnosis of C difficile infection (CDI) requires the presence of compatible symptoms and microbiologic confirmation of C difficile toxin in stool. A two-step testing algorithm consisting of a sensitive initial screening test that detects the organism (nucleic acid amplification test [NAAT] or glutamate dehydrogenase enzyme immunoassay [GDH EIA]) followed by a confirmatory specific test that demonstrates presence of C difficile toxin in stool (EIA) is recommended.
  • A negative screening test excludes C difficile infection in most cases.
  • A reactive screen and reactive confirmatory test for C difficile toxin confirm infection and the presence of C difficile toxin.
  • A reactive screen with negative confirmatory toxin assay is an indeterminate result. Many such cases are colonized but do not have disease. Clinical judgement is needed in such cases due to limited sensitivity of toxin assays.
  • In settings where two-step testing is not available, judicious use of testing and careful evaluation of the clinical context is essential because a positive test result could reflect colonization or disease. A positive result in this context should usually be managed as a true positive. Consultation with an expert in the field should be considered.
• Testing of stool samples from asymptomatic patients or from patients whose symptoms have resolved is not recommended. A positive test is of no clinical significance in these patients.

Treatment (Table 1)

Initial episode

• Non-severe illness. Not all children with non-severe CDI require targeted treatment. When the illness is precipitated by antibiotics, these should be stopped, if possible. For cases with milder symptoms where precipitating antibiotics are stopped and C difficile-targeted treatment is not being initiated, the parents should be advised to seek help if symptoms worsen or a child has not improved within 48 hours. When C difficile-targeted treatment is administered, either oral vancomycin or oral metronidazole are appropriate options.
• Severe illness. The treatment of choice for severe, uncomplicated CDI (along with discontinuing the presumed offending antibiotic, if possible) is oral vancomycin.
• Severe, complicated CDI (with ileus, megacolon, shock, peritonitis, or hypotension). Treat with vancomycin and with intravenous metronidazole.

First recurrence

• In most children, first recurrences can be treated with the same regimen used in the first episode. In children with significant immunocompromising or other underlying conditions who received metronidazole for their first episode, treatment with vancomycin should be administered.

Second or later recurrences and secondary prophylaxis

• Second or later recurrences should be treated with vancomycin, using a tapered regimen.
• Fidaxomicin may be considered on a case-by-case basis for children older than 6 months of age.
• For intractable cases or multiple recurrences, fecal microbiota transplantation or an experimental equivalent may be considered on a case-by-case basis. As fecal microbiota transplantation is not readily available in most jurisdictions in Canada, consultation with a local expert is advised.
• Secondary vancomycin prophylaxis may be considered on a case-by-case basis in consultation with an expert for children with a history of CDI and risk factors for recurrence who require systemic antibiotic therapy.

Acknowledgements

This position statement was reviewed by the Hospital Paediatrics Section Executive and the Community Paediatrics and Nutrition and Gastroenterology Committees of the Canadian Paediatric Society. It was also reviewed by the Association of Medical Microbiology and Infectious Disease Canada (AMMI Canada), Pediatric Committee.

CANADIAN PAEDIATRIC SOCIETY INFECTIOUS DISEASES AND IMMUNIZATION COMMITTEE (2025-2026)

Members: Michelle Barton MD (Chair), Eugene Ng MD (Board Representative), Laura Sauvé MD (Past Chair), Ari Bitnun MD MSc, Sergio Fanella MD, Justin Penner MD (Past Member), Jeannette Comeau MD MSc
Liaisons: Dorothy Moore MD (National Advisory Committee on Immunization), Ari Bitnun MD (Canadian Paediatric and Perinatal HIV/AIDS Research Group), Isabelle Viel-Thériault MD (Committee to Advise on Tropical Medicine and Travel), Marina Salvadori MD (Public Health Agency of Canada), Sean O’Leary (American Academy of Pediatrics, Committee on Infectious Diseases), Rupeena Purewal MD (Immunization Monitoring Program, ACTive), Cora Constantinescu MD (Association of Medical Microbiology and Infectious Disease Canada, Pediatric Committee)
Principal authors: Ari Bitnun MD MSc, Jeannette Comeau MD MSc, Justin Penner MD, Michelle Barton MD

Potential Conflict of Interest
Dr. J. Comeau reported having been a co-investigator on clinical trials with the following pharmaceutical companies, but received no direct compensation: Pfizer, GlaxoSmithKline Inc, ModernaTX Inc, Merck Canada Inc, CanSino Biologics Inc. & Barinthus Biotherapeutics (previously Vaccitech Limited), Entos Pharmaceuticals Inc, VBI Vaccines Inc, GlaxoSmithKline Biologicals, Vaccine and Infectious Disease Organization- International Vaccine Centre (VIDO-InterVac), Sanofi Pasteur Inc. No other disclosures were reported.

Funding
There is no funding to declare.

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Disclaimer: The recommendations in this position statement do not indicate an exclusive course of treatment or procedure to be followed. Variations, taking into account individual circumstances, may be appropriate. Internet addresses are current at time of publication.