Clostridium difficile has long been recognized as the leading cause of antibiotic-associated infection in adults hospitalized.1 However, over the past few decades, Clostridium difficile infection (CDI) has been reported with increased frequency in the community as well as in the pediatric population. Furthermore, the emergence of a new hypervirulent strain, referred to as North American pulse type 1 strain (NAP1), has been associated with severe illness.
It is well known that CDI often occurs after antibiotic exposure, which disturbs the normal bowel microbiota and allows for overgrowth of C. difficile. Proton-pump inhibitors are another risk factor for CDI. A local production of toxins leads to bowel inflammation and secretory diarrhea. A progression of this inflammation results in colitis.2 The diagnosis and treatment of CDI in children, especially in infants and young children, is not completely understood, which creates a diagnostic challenge for the pediatrician.
The first reported discovery of C. difficile was in infants. In 1935, Hall and O'Toole discovered a gram-positive, spore-forming bacillus in the stool of 4 of 10 healthy neonates who were breast-fed.3 It was named Bacillus difficilus due to the difficulty in isolating and studying the pathogen. It was not until 1978 that the link between exotoxin produced by C. difficile with pseudomembranous colitis and diarrheal illness in adults receiving antibiotics was established.4 Over the past few decades, C. difficile has become the most common antibiotic-associated infection worldwide, accounting for 12.1% of health care associated infections.5
Incidence and Epidemiology
CDI is an infection that should be reported to state health departments, where active tracking is performed through the Centers for Disease Control's emerging infection program (EIP) health care-associated infections community interface.
In 2011, an active population and laboratory-based surveillance study was conducted across 10 geographic locations in the United States.1C. difficile was responsible for almost 500,000 cases and 29,000 deaths. Of those cases, 65.8% were hospital-associated infections, mostly in adults.1 The epidemiology of CDI in children has been changing since the 1970s. A trend similar to the one seen in adults has been observed in children. This includes (1) a higher incidence of CDI in hospitalized children, (2) the emergence of community-acquired infections, and (3) a more severe degree of the infection with the NAP1 strain.1
Burden of CDI
The burden of CDI in children has been described in several studies. A study6 of children admitted to a tertiary care children's hospital in 2002 found that hospital-acquired diarrhea was the third most common nosocomial infection and C. difficile was the most commonly identified cause (32%). Another large retrospective review of 4,895 children at 20 US children's hospitals demonstrated an increase in the incidence of CDI from 2 to 4 cases per 1,000 admissions between 2001 and 2006.7 A similar result was observed in a retrospective cohort study using the Healthcare Cost and Utilization Project Kids' Inpatient Database for the years 1997, 2000, 2003, and 2006.8 A rise in pediatric CDI hospitalization from 7.24 to 12.8 cases per 10,000 hospitalizations was observed. The highest incidence of CDI-related hospitalizations occurred among children age 1 to 4 years.8 A more recent study showed a steady rate of CDI in children. This review, conducted using data from the CDC's National Hospital Discharge Surveys from 2001 to 2010, showed that rates of CDI remained relatively unchanged in pediatric patients over the study period (1.2/1,000 pediatric discharges in 2001 and 2010).9
The NAP1 strain has also been identified among children. About 20% of the samples from C. difficile toxin-positive stool samples at two tertiary care children's hospitals were identified as NAP1.10 CDI related to NAP1 strain is seen in children without exposure to a health care facility or antibiotics.
C. difficile is a fastidious gram-positive bacilli and spore-forming obligate anaerobe. It is ubiquitous in nature and is found in soil, hospital environments, and childcare and nursing home settings.11 It exists either as a vegetative form or spore form. During periods of environmental stress, the C. difficile bacterium initiates the process of sporulation. The spores are resistant to oxygen stress, temperature extremes, and desiccation. In a hospital environment, the spores may be resistant to the effects of alcohol-based hand sanitizers. The spore form represents a reservoir that can continue to persist in the environment.
Once the ingested spores reach the colon, they convert into a vegetative form and are capable of producing toxins that are responsible for the disease (Figure 1).
Events in the pathogenesis of Clostridium difficile infection. C. difficile infection begins with dysbiosis created by antibiotics, proton-pump inhibitors, or surgery, allowing colonization of toxigenic strains of C. difficile. Disease is caused by toxin A and B production. (A) These toxins bind to receptors on the enterocytes. (B) This causes disorganization of actin microfilaments resulting in (C) opening of tight junctions and destruction of enterocytes. (D) Toxin A diffuses through the open junction and induces activation of neutrophils. The consequence is increased permeability and damage of enterocytes from local inflammation, resulting in the clinical symptoms of C. difficile infection. IgA, immunoglobulin A; MAMP, microbial-associated molecular patterns; PPI, proton-pump inhibitor; SCFA, short-chain fatty acid.
Colonization in Older Children and Adults
Colonization is inhibited by regular intestinal microbiotas, which are believed to compete for intestinal nutrients and space.12 Improved understanding of the human microbiome has helped better explain the causation of CDI. Normal gut microbial colonies resist the overgrowth of pathogenic microbes (ie, colonization resistance).12 Antibiotic administration alters the normal flora and facilitates C. difficile colonization in part through alteration of in vivo bile acid metabolism.
Neonates and young children have higher rates of colonization with toxin-producing C. difficile strains, yet they rarely present with any symptoms. Experiments in newborn rabbits suggest that protection against disease may result from lack of receptors for toxin A.13 The immaturity of the toxin receptor sites may also play a role in the absence of disease in neonates.
Toxin Production and Disease
Presence of a toxigenic C. difficile strain under favorable conditions produces toxins. Both toxin A and B are believed to be pathogenic, but toxin B is 10 times more potent than toxin A.14 A third toxin, known as the binary toxin, is produced by some strains of C. difficile but its role in the pathogenesis is not clear.
The toxins are large glucosyltransferases produced by the vegetative form of the organism. These toxins are taken up by the cells of mucosal epithelium through the process of receptor-mediated endocytosis (Figure 1). They act at the level of the epithelial cells and produce effects by two pathways. Toxins A and B cause disruption of enterocyte's actin cytoskeleton. This change in enterocyte structure leads to epithelial cell destruction and loss of cell-to-cell tight junctions between enterocytes. Toxin A also induces activation of neutrophils and results in local inflammation. Release of proinflammatory cytokines, including interleukin-6 and interleukin-8, from enterocytes causes further damage to the intestinal mucosa. Both toxins increase permeability through enterocytes, and local inflammation leads to mucosal damage, which results in the clinical symptoms of CDI.15
Pathogenesis of Recurrent Clostridium difficile Infection
About 20% to 30% of patients affected develop a recurrence of symptoms after the first episode of CDI.16 Patients at risk of recurrent CDI lack the ability to restore bowel microbiota to normal baseline, which results in either reinfection or overgrowth of residual infection after the first round of therapy. The degree of immunity from antibody production is also an important determinant of protection against recurrence. Infection with the epidemic NAP1/BI/027 strain of C. difficile is associated with an increased risk for recurrence. Factors associated with recurrence with NAP1 strain are due to the presence of (1) additional toxins, such as binary toxin, (2) intrinsic antibiotic resistance (eg, to quinolones), and (3) factors of spore biology.
C. difficile is transmitted via ingestion of spores of the organism. Person-to-person spread via the fecal-oral route and environment-to-person contact spread are both important in the spread of this infection in the health care environment. Objects likely to harbor C. difficile are those contaminated with feces, such as toilet seats and sinks, but it can also be isolated from the hands of asymptomatic hospital personnel. Stethoscopes and electronic rectal thermometers have been reported as vectors for C. difficile transmission when not effectively cleaned after use on a patient with CDI.17 The hardy spores of C. difficile render eradication in hospital environment difficult through routine cleaning and disinfection. Spores can survive in the environment for up to 5 months.18
C. difficile causes numerous clinical manifestations that depend on the nature of the strain and host characteristics. There are four possible outcomes after a child becomes colonized with C. difficile: (1) asymptomatic carriage, (2) acute mild to moderate self-limiting infection, (3) severe infection with cases of pseudomembranous colitis or fulminant colitis, and (4) recurrent infection.
Neonates and young infants have high rates of colonization but rarely have symptoms. Genomic analyses have demonstrated that the newborn's gut is colonized with maternal and placental microbiome at the time of birth rather than being sterile.19C. difficile carriage rates average 37% for neonates age 0 to 1 months and 30% for infants between ages 1 and 6 months.20 At age 6 to 12 months, approximately 14% of children are colonized with C. difficile, and by age 3 years the rates are similar to that of nonhospitalized adults (0%–3%).21 A prospective screening study for C. difficile in children younger than age 2 years revealed colonization rates of 33% overall.22 Admission to a neonatal intensive care unit is an important risk factor for colonization. Other factors, such as vaginal delivery, premature rupture of membranes, and previous administration of antimicrobial agents, have little effect on carriage rates. Infants who have been breast-fed have lower rates of carriage compared with infants who have been formula-fed (14% vs 30%, respectively).23
This asymptomatic carriage confounds the diagnosis of diarrhea in infants because when tested they will be positive for C. difficile toxin, but this may not reflect causality. A lower rate of asymptomatic colonization is seen in older children and adolescents.
Mild to moderate disease. Watery diarrhea with or without mucous occurs in 90% to 95% of cases and bloody diarrhea in 5% to 10%.24 Most of these children develop a self-limiting diarrheal illness, often accompanied by fever, abdominal cramping, and nausea. Typically, the symptoms begin while the child is taking an antibiotic or in the hospital; however, the symptoms may not occur until weeks after stopping the antibiotic. Rarely, children develop pseudomembranous colitis (PMC) or chronic diarrhea.
Severe CDI. Fulminant colitis is rare in children and occurs more frequently in neutropenic children with leukemia or in children with inflammatory bowel disease (IBD). Bowel perforation with peritonitis is associated with high morbidity and mortality.25 Other bowel-related complications include rectal prolapse and pneumatosis.
Extraintestinal manifestations. Extraintestinal manifestations of C. difficile are extremely rare, but cases of bacteremia, osteomyelitis, reactive arthritis, and splenic abscesses have been reported.26
CDI in children with cancer. Children with cancer have a higher rate of colonization, symptomatic infection, and recurrence.27 In an analysis of 3 nonconsecutive years of data from the Kids' Inpatient Database (2000, 2003, 2006), children with cancer accounted for 21% of all CDI cases, and the rates of CDI were 15 times higher in children with cancer compared to those without.28 One study29 found that approximately 33% of pediatric oncology patients tested upon hospital admission were colonized with C. difficile and more than 50% remained colonized upon retesting 20 weeks later. Moreover, the recurrence rate of CDI in pediatric cancer patients was about 30%.30
CDI in children with IBD. This special group of children has a higher rate of asymptomatic colonization of C. difficile. Asymptomatic carriage in children with clinically inactive IBD in the outpatient setting has been reported at 17%, compared with 3% in children without IBD. CDI has also been reported to be increased in more severe and active IBD.31,32 It is possible that the underlying dysbiosis with decreased diversity of bowel microbiota found in IBD predisposes to the loss of colonization resistance to C. difficile, leading to increased rates of CDI in this population.
Pediatricians are often faced with the challenge of differentiating between IBD exacerbation and CDI. The higher rate of colonization in children with IBD and the high sensitivity of the polymerase chain reaction assay, which is commonly used for diagnosis, complicate the appropriate diagnosis. CDI testing in children with IBD should be reserved for cases with more than 3 loose stools in a 24-hour period, similar to other pediatric patients.
The diagnosis of CDI is based on the presence of compatible clinical symptoms coupled with laboratory evidence of the infection. The clinical symptoms are defined as presence of 3 or more loose, watery stools for at least 24 hours or presence or fluid content of stools in excess of 10 mL/kg per day in a child. A positive test is defined as detection of the C. difficile organism or its toxin genes, or detection of C. difficile toxin using an enzyme immunoassay. Detection of C. difficile in the absence of symptoms does not meet the criteria for a diagnosis of CDI. The stool specimens submitted for C. difficile testing should be fresh and of liquid consistency. Specimens should be stored at a temperature of <4°C because the toxin rapidly degrades at room temperature. Diagnosis can also be made in patients with diarrheal symptoms by using lower gastrointestinal endoscopy to visualize pseudomembranes in the colon, but it rarely performed for this sole purpose.33
When to Test
Testing is recommended in a child age 2 years or older who is at risk of CDI, such a child with antibiotic exposure in the past 2 months or with at least 3 or more loose watery stools within the a 24-hour period.
Asymptomatic colonization is common in children younger than age 1 year, so testing for C. difficile should not be performed routinely in this age group and other causes for diarrhea should be sought.
Testing for C. difficile in the community without antibiotic exposure is appropriate in a child with colitis when initial testing for other bacterial pathogens is unrevealing.
What Test to Use
Various methods and strategies are used to test for CDI. In general, 90% of CDI cases can be diagnosed with a single specimen.34 Nucleic acid amplification tests (NAATs) that detect toxin A (tcdA) or B (tcdB) genes, often by polymerase chain reaction, are currently used by most laboratories.35 The rates of CDI have increased by 50% or more in hospitals that have adopted NAAT assays because of their higher sensitivity.36 NAAT assays are rapid, specific, and more sensitive than enzyme immunoassays (EIAs).
EIAs detect toxin A and B or the glutamate dehydrogenase (GDH) antigen. They are also commonly used for the clinical diagnosis of CDI. EIAs for GDH offer improved sensitivity but lower specificity because GDH is present in both toxigenic and nontoxigenic strains of C. difficile. EIA for GDH offers the advantages of rapid turnaround time and ease of use. Some laboratories prefer it due to lower cost as compared with NAAT. The high negative-predictive value of the GDH assay makes it useful as a screening tool. In many hospitals, two-step algorithms have been developed using GDH detection as an initial rapid screening step, followed by toxin detection by NAAT if the screen in positive. This two-step method may be preferred for rapidity of reporting negative results and in decreasing false-positive results when a toxin assay is used alone.37
The cell cytotoxicity neutralization assay has historically been considered the gold standard for the diagnosis of CDI. A positive cell cytotoxicity neutralization assay test requires cytopathic changes in 50% or more of exposed cells. This test is highly specific, but it has sensitivity of only 67%,38 requires skilled personnel to interpret the findings in tissue culture, and has a turnaround time of approximately 72 hours, limiting its use.
Stool culture is rarely used in clinical practice for the diagnosis of CDI. Although culture is highly sensitive and specific, it requires selective media to differentiate toxigenic from nontoxigenic strains of C. difficile. Stool culture is generally reserved for epidemiologic investigations.
Test-of-cure in the absence of symptoms is not recommended, as a false-positive result may lead to unnecessary retreatment with antibiotics.
Colonoscopy can be helpful in the diagnosis of a seriously ill child when CDI is suspected but cannot be proven by standard laboratory testing. If PMC seen on examination and clinical symptoms are consistent, the diagnosis of CDI can be made. PMC has a characteristic appearance of yellowish-white raised plaques that are usually 2 to 10 mm in diameter.
Treatment of CDI in a child consists of discontinuation of the offending antimicrobial agent when possible. Most children with mild disease do not require anti-CDI therapy and the symptoms usually resolve within 7 to 10 days. Those with prolonged symptoms or more severe disease will require specific treatment (Table 1) based on published guidelines.39
Treatment of Clostridium difficile Infection
The recommended treatment for an initial episode of CDI and first recurrence of mild to moderate infection is oral metronidazole.39 Oral vancomycin is indicated in children with severe disease who are critically ill and hospitalized in the intensive care unit, children with underlying intestinal disease, or those who are unresponsive to metronidazole therapy. Vancomycin is not effective if given intravenously. For children with severe disease and complications such as shock or ileus, addition of intravenous metronidazole to oral vancomycin therapy is recommended. Orally administered vancomycin is the only treatment for CDI in children approved by US Food and Drug Administration (FDA);40 however, it is reserved for complicated cases in response to concerns over the emergence of vancomycin-resistant Enterococcus species.
The duration of therapy for any regimen should be 10 days, with most patients demonstrating clinical improvement within 1 to 2 days of initiation of therapy, and resolution of diarrhea within 4 to 5 days. Toxin testing as a routine follow-up study is not recommended.
In addition to antimicrobial therapy, supportive care with fluid and electrolytes should be provided. Use of antimotility drugs should be avoided with C. difficile infections due to the associated risk of developing ileus or toxic megacolon.
Other antimicrobial agents with activity against CDI include fidaxomicin, nitazoxanide, and rifaximin. In 2011, the FDA approved the use of fidaxomicin for the treatment of CDI in adults.41 It is a monocyclic antibiotic and acts as an RNA polymerase inhibitor. It is bactericidal against C. difficile. In a large, multicenter, randomized phase III trial, fidaxomicin was noninferior to vancomycin for the treatment of CDI (clinical cure, 88.2% vs 85.5%).42 Recurrent CDI within 4 weeks of clinical cure was significantly less in fidaxomycin-treated patients.42 Studies in children are ongoing.
The pathogenesis of CDI is mainly a change in the normal bacterial flora of the gastrointestinal tract, so adjunctive therapies that promote restoration of normal flora have received increasing attention. One of the treatment options is fecal microbiota transplantation (FMT). In FMT, stool from a healthy donor is administered to a patient with severe or relapsing CDI via colonoscopy or oral capsule in an effort to restore normal intestinal flora. Studies in adults are promising,43,44 and FMT is considered a safe and effective method for CDI treatment. Data in children are lacking at this time.
Probiotics have been studied alone or in combination with antibiotics for the treatment of CDI but the data are conflicting. Probiotic treatment of children with CDI has not been well studied.
Isolation of children with CDI in private rooms and requiring staff to wear gloves and gowns has become standard infection-control practice to limit the transmission of C. difficile. Hand-washing with soap and water is more effective then use of alcohol-based sanitizers.45
In addition, bleach is being used for cleaning the hospital rooms of patients with CDI, either as a terminal cleaning when the patient is discharged or transferred from the room, or on a daily basis. Other methods of environmental disinfection that are currently being used include hydrogen peroxide vapor and ultraviolet light, both of which appear effective but are expensive and increase the turnaround time for room occupancy.
Antimicrobial stewardship programs focusing on reducing unnecessary antimicrobial use and restricted access to specific agents are a critical component of the efforts to reduce these risks of CDI.
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- Bartlett JG, Chang TW, Gurwith M, et al. Antibiotic-associated pseudomembranous colitis due to toxin-producing clostridia. N Engl J Med. 1978;298:531–534. doi:10.1056/NEJM197803092981003 [CrossRef]
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- Dominguez SR, Dolan SA, West K, et al. High colonization rate and prolonged shedding of Clostridium difficile in pediatric oncology patients. Clin Infect Dis. 2014;59:401–403. doi:. doi:10.1093/cid/ciu302 [CrossRef]
- De Blank P, Zaoutis T, Fisher B, Troxel A, Kim J, Aplenc R. Trends in Clostridium difficile infection and risk factors for hospital acquisition of Clostridium difficile among children with cancer. J Pediatr. 2013;163(3):699–705. doi:. doi:10.1016/j.jpeds.2013.01.062 [CrossRef]
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Treatment of Clostridium difficile Infection
|Category of CDI
|Mild to moderate
||30 mg/kg/day in four divided doses
Maximum 2 g/day × 10 days
Oral vancomycin plus
||40 mg/kg/day in 4 divided doses × 10 days
||30 mg/kg/day in four divided doses × 10 days
|More than one recurrence/severe disease
||Tapered/pulse oral vancomycin
||125 mg PO qid × 10 days, then 125 mg PO bid × 7 days, then 125 mg PO qd × 7 days, then 125 mg PO qod or q3d × 14–28 days
200 mg twice daily (adults) × 10 days
500 mg twice daily (adults) × 10 days
200 mg three times a day (age ≥3 years) × 10 days
||125 mg PO twice daily for 7–10 days after treatment