Etiology

C. difficile is a gram-positive, anaerobic bacillus capable of forming a spore that is resistant to killing by alcohol. Organisms causing symptomatic disease produce one or both of the following: toxin A and toxin B. These toxins affect intracellular signaling pathways, resulting in inflammation and cell death. The cytotoxic Binary toxin, an AB toxin, is not present in the majority of strains but has been detected in recent epidemic strains.

Epidemiology

The incidence of CDI increased 48%, from 2.5 to 3.7 cases/1000 pediatric admissions, between 2001 and 2006. The age group most affected was 1 to 5 yr old children, with an 85% increase in CDI rates. Concurrent with this rise in incidence, disease severity has also increased, as evidenced by changes in colectomy and mortality rates in adults (thus far increases in colectomy and mortality rates have not been observed in the pediatric population).

A hypervirulent strain, denoted NAP1/BI/027, has acquired fluoroquinolone resistance, leading to outbreaks throughout North American and European hospitals. This strain produces binary toxin and exhibits 16- and 23-fold increases in the production of toxins A and B production, respectively. The specific role of this hypervirulent strain in the changing epidemiology of CDI is not yet completely understood.

Asymptomatic carriage occurs with non–toxin-producing strains as well as in neonates, who may lack the toxin receptor. Carrier frequency rates of 50% may occur in children younger than 1 yr but decline to 3% by age 2. Carriers can infect other susceptible individuals.

Risk factors for CDI include use of broad-spectrum antibiotics, hospitalization, gastrointestinal surgery, inflammatory bowel disease, chemotherapy, enteral feeding, proton pump–inhibiting agents, and chronic illness. Once thought to be exclusively a nosocomial, iatrogenic disease, CDI is increasingly recognized in the community. Half of all community-acquired cases occur in the pediatric population, and 35% of these infections occur with no history of antibiotic exposure.

Pathogenesis

Disease is caused by gastrointestinal infection with a toxin-producing strain. Any process that disrupts normal flora, impairs the normal gastrointestinal immune response (e.g., inflammatory bowel disease [IBD]), or inhibits intestinal motility may lead to infection. Normal bowel flora appears to be protective, conferring “colonization resistance.”

By affecting intracellular signaling pathways and cytoskeletal organization, toxins induce an inflammatory response and cell death, leading to diarrhea and pseudomembrane formation. Antibodies against toxin A have been shown to confer protection from symptomatic disease, and failure of antibody production has been shown to occur in patients with recurrent disease.

Clinical Manifestations

Infection with toxin-producing strains of C. difficile leads to a spectrum of disease ranging from mild, self-limited diarrhea to explosive, watery diarrhea with occult blood or mucous, to pseudomembranous colitis, and even death. Pseudomembranous colitis describes a bloody diarrhea with accompanying fever, abdominal pain/cramps, nausea, and vomiting. Rarely, small gut involvement, bacteremia, abscess formation, toxic megacolon, and even death can occur.

Symptoms of CDI generally begin less than a week after colonization and may develop during or weeks after antibiotic exposure. They are generally more severe in certain populations, including patients receiving chemotherapy, patients with chronic gastrointestinal disease (e.g., IBD), and some patients with cystic fibrosis.

Diagnosis

CDI is diagnosed by the detection of a C. difficile toxin in the stool of a symptomatic patient. Most patients present with a history of recent antibiotic use, but the absence of antibiotic exposure should not dissuade the astute clinician from considering this diagnosis and ordering the appropriate test.

The standard for toxin detection is the tissue culture cytotoxicity assay. This assay detects only toxin B and requires 24-48 hr. It has been supplanted in most clinical laboratories by the enzyme immunoassay, which requires less time, a lower level of expertise, and less expense. The enzyme immunoassay is a same-day test for one or both toxins with sufficient specificity (94-100%) but less than ideal sensitivity (88-93%). Toxin detection rates shift by age group, from predominantly toxin A in neonates to predominantly toxin B in adolescence. Accordingly, testing for both toxins is recommended in pediatric populations to reduce the rate of false-negative results.

Stool culture is a sensitive test, but it is not specific, as it does not differentiate between toxin-producing and non–toxin-producing strains. Pseudomembranous nodules and characteristic plaques may be seen on colonoscopy or sigmoidoscopy.

Treatment

Initial treatment of CDI involves discontinuation of any nonvital antibiotic therapy and administration of fluid/electrolyte replacement. For mild cases, this treatment may be curative. Persistent symptoms or moderate to severe disease warrants antimicrobial therapy directed against C. difficile.

Oral metronidazole (20-40 mg/kg/day by mouth [PO] divided every 6-8 hr for 7-10 days) works well in mild to moderate infection. It is the least expensive approach, though studies comparing it to vancomycin have shown a significantly longer time to symptom resolution as well as a higher failure rate when metronidazole is use to treat severe disease. Vancomycin (25-40 mg/kg/day PO divided every 6 hrs for 7-10 days) is the only therapy approved by the U.S. Food and Drug Administration for use against infection with C. difficile. Vancomycin exhibits ideal pharmacologic properties for treatment of this enteric pathogen, as it is not absorbed in the gut. This agent is suggested as a first-line agent for severe disease as manifested by hypotension, peripheral leukocytosis, or severe pseudomembranous colitis. A concern about using it as first line therapy in all cases is the potential for emergence of vancomycin-resistant enterococci (VRE). Nitazoxanide and fidaxomicin are other agents that are effective in treating CDI in adults.

Prognosis

The response rate to initial treatment of CDI is greater than 95%; however, both the treatment failure rate and recurrence rate have increased over the last two decades. Additionally, the risk of subsequent reappearance increases with each recurrence.

Initial recurrence rates are between 5% and 30%, and CDIs generally recur within 4 wk of treatment. Some recurrences are due to incomplete eradication of the original strain, and others to reinfection with a different strain. Treatment for the initial recurrence involves retreatment with the original antibiotic course.

Multiple recurrences of CDI may be due to a suboptimal immune response, failure to kill organisms that have sporulated, or failure of delivery of antibiotic to the site of infection in the case of ileus or toxic megacolon. In the case of the first two causes, treatment with pulsed or tapered vancomycin has been shown to decrease recurrence rates. In addition to this approach, other antibiotics (rifaximin or nitazoxanide), toxin-binding polymers (Tolevamer), fecal transplantation, and probiotics (Saccharomyces boulardii or Lactobacillus GG) have been used. Though not well studied in children, S. boulardii has been shown to significantly decrease recurrence rates when used as an adjunct to vancomycin therapy in adults. Because failure to manifest an adequate antitoxin immune response is associated with a higher frequency of recurrent CDI, intravenous immune globulin (IVIG) has been used to treat recurrent disease. In the case of ileus or toxic megacolon, an enema of vancomycin may be used to directly place the antibiotic at the site of infection, although most often intravenous therapy is first attempted in this circumstance.

It is important to recognize that postinfectious diarrhea may be due to other causes. Examples are post-infectious irritable bowel syndrome, microscopic colitis, and IBD. A test of cure is not recommended in the asymptomatic patient.

Prevention

Strategies for prevention of CDI include the following: recognition of common sites of acquisition (hospitals, childcare settings, extended care facilities), effective environmental cleaning (i.e., use of chlorinated cleaning solutions), appropriate antibiotic prescription practices, cohorting of infected patients, and proper handwashing with soap and water.