Clostridium difficile is the most common cause of healthcare-associated diarrhea in Western countries. Its pathogenic potential was established in landmark studies in the 1970s demonstrating its strong association with antibiotic-associated pseudomembranous colitis . Subsequently, it was recognized that the development of C. difficile infection (CDI) usually requires two events: contact with the organism, which was most likely to occur in the hospital or long-term care facility; and antibiotic-induced perturbation of the normal intestinal microbiota, which, when intact, prevents stable colonization of C. difficile through a phenomenon known as ‘colonization resistance’. Once C. difficile establishes its presence in the large intestine, it injures the colonic epithelium by elaborating two potent enterotoxins labeled toxin A and toxin B, without which the organism is nonpathogenic.
The past decade has witnessed a dramatic increase in the incidence of CDI in both adults and children, with an estimated annual cost to American healthcare facilities of nearly $5 billion . It is thus imperative for all clinicians caring for children to be familiar with this entity. The following will review the recent epidemiological evolution of CDI, particularly in children, the risk factors for acquiring CDI in the pediatric age group, and therapeutic options.
CHANGING EPIDEMIOLOGY OF CLOSTRIDIUM DIFFICILE INFECTION
The epidemiology of CDI has changed dramatically in recent years. Over the past decade, its incidence has more than doubled in adults and the number of CDI-related hospitalizations has increased by nearly 300%; only recently has this increase tapered . A major feature of this changing epidemiology has been an increase in CDI among patients previously believed to be at low risk for the disease, specifically patients in community or outpatient settings [4,5]. This was highlighted in a recent publication from the Centers for Disease Control and Prevention (CDC) in 2010, which reported that 52% of cases of CDI were present upon hospital admission, although most were determined to be in patients with recent healthcare exposure [6▪]. Still, there has been an accumulating recognition of CDI among patients without any recent healthcare contact, giving rise to new definitions that include community-associated disease . Recent adult studies have reported rates of community-associated CDI around 20% of all of CDI cases .
The changing epidemiology of CDI has occurred largely in parallel to the emergence of a hypervirulent strain of C. difficile, referred to as the ‘NAP1’ strain [5,9]. The first epidemic NAP1 cases were reported from North America between 2000 and 2002 and were associated with a marked increase in morbidity and mortality among affected adults [10,11]. Since then, NAP1 has been identified throughout the world and has been linked to outbreaks in North America, Europe, and Asia .
Epidemiology of Clostridium difficile infection among children
Similarly to findings in adult patients, several studies have shown a rise in CDI among children [12–18]. The hypervirulent NAP1 strain has also been identified among children [19–22], isolated from 19.4% of consecutive C. difficile toxin-positive stool samples obtained from children hospitalized at two tertiary care children's hospitals [19,20]. Surveillance data for CDI in children are limited, but several studies have used large administrative databases to evaluate CDI-related hospitalizations among multicenter cohorts of hospitalized children [12,13,15,16,23]. The first of such multicenter studies was performed among 4895 hospitalized children at 22 US children's hospitals and found an increase in CDI from 2.6 to 4 cases per 1000 admissions between 2001 and 2006 . Similar results were found using other large multicenter cohorts [15,16].
Several studies additionally have reported a rise in CDI among children in the community, including those presenting for outpatient evaluation of diarrhea or undergoing evaluation of previously undiagnosed gastrointestinal complaints with outpatient colonoscopy [4,14,17]. A prospective cohort study evaluating children presenting with diarrhea to a pediatric emergency department found that C. difficile was the most common bacterial pathogen identified . In addition, evaluation of a cohort of 181 hospitalized children found that 25% of cases had no recent healthcare exposure and thus were community-associated [25▪]. These observations must be balanced against those of a more recent study evaluating the cause of diarrhea in children presenting to an emergency department, which found that rates of C. difficile in stool samples were similar between cases and controls, particularly among those aged less than 36 months . This finding underscores the importance of testing only patients exhibiting gastrointestinal symptoms and highlights the need for further research in community-associated CDI among children.
Although mild to moderate diarrhea is the most common manifestation of CDI, complications such as toxic megacolon, sepsis, and death, while relatively rare in children, continue to be reported [26–28]. An evaluation of the epidemiology of severe CDI among a cohort of hospitalized children at two pediatric centers found that CDI-related complications, including toxic megacolon, gastrointestinal perforation, and need for surgical intervention due to CDI occurred in fewer than 2% of the cohort, although transfer to the ICU within 1–2 days of diagnosis was relatively common (17%) . Outcomes related to CDI in children are poorly characterized; however, the presence of CDI has been associated with longer lengths of stay, increased hospital charges, and higher rates of in-hospital mortality among hospitalized children .
RISK FACTORS FOR CLOSTRIDIUM DIFFICILE INFECTION IN CHILDREN
Major risk factors for CDI include increased exposure to C. difficile spores, usually from prolonged hospital stays, alterations in the lower intestinal microbiota, and factors that decrease host defenses, such as impaired immune status [7,29]. Most authorities recognize previous antibiotic exposure as the single most important risk factor for CDI in adults and children, and nearly all antibiotics have been associated with CDI . Dedicated pediatric studies evaluating risk factors for CDI in children remain limited, although the majority of studies have reported an association between both antibiotic exposure and prior hospitalization and CDI in children [25▪,31].
A more recent study evaluating risk factors for CDI among hospitalized children at a tertiary care children's hospital identified additional patient level factors, including solid organ transplantation and presence of a gastrostomy or jejunostomy tube [25▪]. Indeed, the presence of a chronic comorbid condition is common in children with CDI, likely related to the combination of frequent hospitalizations and exposure to antibiotics and immunosuppressive therapies. C. difficile is frequently isolated from children with inflammatory bowel disease (IBD) [16,32,33] and CDI has been associated with increased IBD disease severity and escalation of IBD-directed therapy following infection . In addition, children with CDI and IBD have been found to have higher rates of CDI recurrence  and treatment failure  compared with patients with CDI but no IBD. CDI is also commonly reported among children with cancer or receiving immunosuppressive therapies [35,36]. In fact, data from a large administrative database containing a multicenter cohort of hospitalized children indicated that the rate of CDI was 15 times higher among pediatric patients with cancer compared with all other children .
The association between gastric acid-suppressing agents, specifically proton pump inhibitors (PPIs), and increased risk of CDI has gained recent attention following the release of a US Food and Drug Administration (FDA) Drug Safety Alert. Contemporaneously with this release, findings from three meta-analyses suggested that PPIs were associated with at least a two-fold increased risk of CDI among adult patients [38,39,40▪]. Although the mechanism of association is unclear, it has been shown that vegetative forms of C. difficile can survive in gastric contents with an elevated pH . Few pediatric studies were included in the recent meta-analyses and existing data on the association between PPIs and risk of CDI in children are limited. An Italian study evaluating risk factors for CDI among hospitalized children with abdominal pain and diarrhea found that the use of PPIs was significantly associated with CDI after multivariable analysis . Other pediatric studies have not shown an association . Still, given the widespread use of PPI therapy and the compelling findings in adult patients, more judicious use of these agents by pediatricians is warranted.
Therapies for CDI can be divided into those that are antibiotic-based and those that are not. In almost all instances the effectiveness of these interventions has been tested in adults with CDI, with the results extrapolated to children.
The most strongly established antibiotic regimens for both adults and children with CDI remain oral metronidazole and oral vancomycin . Oral vancomycin is not absorbed from the gastrointestinal tract, resulting in intracolonic concentrations that far exceed the minimal inhibitory concentration of C. difficile. Metronidazole is highly absorbed, with little to no drug found in feces after oral administration , but decades of experience have demonstrated that it is curative in most cases of CDI. Until recently, these therapies were felt to be equally effective. Indeed, the randomized, placebo controlled trial by Zar et al. comparing metronidazole and vancomycin documented an equivalent cure rate in adults with mild to moderate CDI (both >90%). However, in those suffering from severe infections, the same study reported greater efficacy in vancomycin recipients (97%) compared with those assigned to metronidazole (76%; P < 0.02) . Vancomycin thus has become the preferred therapy in severe CDI . Concerns previously raised that vancomycin exposure was more likely than metronidazole to promote colonization by vancomycin-resistant enterococci (VRE)  have not been borne out, as studies in adults indicate that both agents result in new acquisition of VRE or prolongation of pre-existing VRE colonization equally .
Recurrent symptoms occur in approximately 30% of adults and children with CDI who initially responded to either metronidazole or vancomycin [20,48], and multiple cycles of debilitating disease afflict approximately half of those with a first recurrence . In most instances, recurrent CDI is due to retained spores which are largely resistant to antibiotic effects, which then germinate to the active vegetative state after the course of therapy is completed. In some cases recurrent symptoms result from infection by a second C. difficile strain . Both mechanisms are potentiated by persistent perturbations of the resident colonic microbiota caused by exposure to the initial inciting antibiotic and worsened by further exposure to metronidazole or vancomycin. There have been no cases documented to date in which recurrence was the result of organisms resistant to either of these two drugs. Hence, most authorities recommend a second course of the original antibiotic to treat the first recurrence, unless the severity of the recurrence warrants vancomycin . It has become common practice to complete the course for recurrent CDI either with taper therapy, in which the dose of medication is gradually reduced to allow restitution of the normal flora, or by pulse therapy, in which antibiotic is administered in cycles to eradicate organisms that have germinated in the absence of drug .
Fidaxomicin was recently introduced for the treatment of adult CDI. The drug is a macrocyclic compound that inhibits bacterial RNA polymerase . Similarly to oral vancomycin, it is poorly absorbed from the gastrointestinal tract and reaches high intraluminal concentrations. Two randomized trials of CDI in adults indicate that the cure rate is noninferior to vancomycin [52,53▪]. The rate of recurrence after a course of fidaxomicin, however, is approximately half that seen with vancomycin [52,53▪], presumably due to the relatively mild effect of the drug on the resident colonic microbiota . The drug is not yet licensed for use in pediatrics, but early trials examining kinetics and safety in children are underway.
Other drugs have been studied in CDI but evidence of their efficacy is less compelling. Nitazoxanide, a thiazolide with broad antibacterial and some antiparasitic activity, is familiar to pediatricians as an option for treating giardiasis and cryptosporidiosis. Studies in CDI have indicated that nitazoxanide results in a cure rate equivalent to metronidazole and vancomycin . These studies have included small numbers of participants, and the role of nitazoxanide in CDI remains uncertain. Rifaximin is a rifamycin compound with activity against C. difficile that reaches high concentrations in the colonic lumen. Like other rifamycins, exposure of C. difficile to rifaximin may result in the rapid emergence of organisms with high-level resistance . Two additional compounds with activity against Gram-positive bacteria, bacitracin and fusidic acid, have been offered to adults with CDI but have been similarly associated with emergence of resistant organisms . Tigecycline, a glycycline with broad-spectrum activity that has been especially useful in treating highly-resistant hospital-acquired bacteria in adults, occasionally has been offered to patients with severe CDI who have failed conventional therapies . The drug has not been widely used in children.
Given the central role that a disturbed colonic microbiota plays in the pathogenesis of CDI, there is an intrinsic logic in attempting to re-establish colonization resistance through the administration of probiotics. The data supporting this practice are scant, however, and a recent systematic review , as well as current C. difficile management guidelines , does not recommend their use. Small studies, however, have been partially supportive. The trial conducted by McFarland et al., for example, randomized 124 adults with CDI to receive standard therapy with or without Saccharomyces boulardii for 4 weeks. In participants who had already experienced at least one recurrence, additional recurrent episodes were significantly reduced in the group receiving probiotics (35 vs. 65%; P = 0.04), but not in those presenting with initial CDI. A second study by many of the same authors  indicated that the incidence of recurrent CDI was reduced when Saccharomyces was administered with high-dose oral vancomycin; no benefit was seen when probiotics were given with lower-dose vancomycin or metronidazole.
A more radical intervention aimed at reconstituting the colonic microbiome in patients with CDI is termed ‘fecal transplantation’. In this procedure, most frequently offered to adults with severe, intractable disease, a suspension of stool from a healthy donor, usually a relative, is administered to the patient either through a gastroscope, by jejunal tube, or by enema. Gough et al. recently culled the fecal transplantation experience from 27 publications and reported a cumulative response rate exceeding 90%.
There is evidence that at least some patients with severe or recurrent CDI may have poor antibody response to C. difficile enterotoxins . Commercial immune globulin preparations, which frequently contain antibodies against C. difficile toxin A and toxin B, have been effective in case series including both adults and children with severe disease [62,63]. Recently, a randomized, placebo-controlled trial tested the effectiveness of a preparation of monoclonal antibodies against C. difficile toxins A and B in adults with CDI . Among 200 participants, those who received the monoclonal antibody preparation experienced significantly fewer recurrences (7 vs. 25%; P < 0.001).
The rise in incidence of CDI over the past decade mandates that pediatricians remain familiar with this disease. The populations at highest risk for infection include children with prolonged healthcare exposure, especially those with inflammatory bowel disease and cancer, but CDI is occurring with increasing frequency among otherwise healthy children in the community. The most established therapies remain oral vancomycin and metronidazole.
Dr Toltzis receives grant support from the Ohio Department of Health.
Conflicts of interest
Dr Sammons reports pending research support for an investigator-initiated study through Merck.
REFERENCES AND RECOMMENDED READING
Papers of particular interest, published within the annual period of review, have been highlighted as:
- ▪ of special interest
- ▪▪ of outstanding interest
Additional references related to this topic can also be found in the Current World Literature section in this issue (pp. 157–158).
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