C. difficile is considered part of the normal flora of infants younger than 1 year and has been isolated from 25% to 50% of neonates and 45% of infants younger than the age of 12 months. Significant toxin B titers may be measured in 25% to 50% of asymptomatic infants. The reasons for asymptomatic carriage in infancy are unknown but may include the absence of toxin receptors, maternal antitoxin, or immature inflammatory responses. C. difficile colonization occurs in only 4% to 18% of older children and is isolated rarely from the stools of healthy adults, although it is a common vaginal species. In one study of self-limited mild diarrhea associated with antibiotic treatment in a group of very young children, most of whom were infants younger than 1 year of age, no correlation of symptoms with C. difficile colonization or toxin was found. Nonetheless, numerous cases of protracted diarrhea occur in infants in whom C. difficile is the only identified pathogen.

C. difficile is implicated most frequently in chronic or colitic diarrhea. In a study of adults with antibiotic-associated diarrheal states, 27% had demonstrable C. difficile toxin. In both adults and children, C. difficile colonization with toxin production is responsible for at least 95% of antibiotic-associated pseudomembranous colitis. Pseudomembranous colitis caused by C. difficile has been reported in settings in which antibiotics have not been used. In addition, rare reports exist of pseudomembranous enterocolitis attributed to other organisms, such as C. perfringens and S. aureus.

C. difficile is a gram-positive, spore-forming obligate anaerobic bacillus resistant to most antibiotics. C. difficile is present in soil and can be cultured from hospital surfaces. Spores may be acquired directly from the environment or by fecal–oral transmission from colonized contacts. It may be isolated from blood agar culture and inoculated into chopped meat broth media made selective by the addition of cycloserine and cefoxitin, followed by subtyping for toxigenic strains. C. difficile produces two exotoxins implicated in the secretory and inflammatory features of enterocolitis. Toxin A is a potent enterotoxin and chemotactic agent causing inflammation and secretion of a hemorrhagic exudate in ligated rabbit ileal loops but having little effect on cultured fibroblast cells used for cytopathic assay. Conversely, toxin B is one of the most potent cytotoxins in cultured fibroblast assays, leading to its diagnostic utility. Although toxin B has been the traditional diagnostic marker, toxin A, usually elaborated in much greater amounts, has been considered the principal agent in the pathogenesis of C. difficile-related diarrhea and colitis. However, the clinical importance of toxin B is supported by the discovery of pathogenic strains of C. difficile in both animal and human hosts that produce toxin B without producing toxin A and by some evidence that the two toxins may act synergistically.

The indigenous, mixed bowel flora form an important host defense mechanism, limiting proliferation and colonization of potential bacterial pathogens. The composition of the bowel flora is kept remarkably constant with a thousandfold predominance of anaerobic bacteria, despite a great variety of dietary and physiologic changes. The ability of the indigenous flora to limit proliferation or exclude colonization of pathogenic bacteria is called colonization resistance and is important in protecting the host at the gut interface with the environment.

Oral or intravenous antibiotic agents that produce fecal levels sufficient to alter the bowel flora, particularly antibiotics active against the indigenous anaerobic population, reduce the colonization resistance of the intestinal lumen to C. difficile. C. difficile may be harbored normally in limited numbers or may be introduced from environmental reservoirs, vaginal sources, other colonized contacts, or environmental surfaces. The relative resistance of C. difficile to most conventional antibiotics allows it to proliferate and elaborate its cytopathic enterotoxins associated with invasiveness, inflammation, and secretion. The superficial inflammation may progress to mucosal necrosis and exudation of protein and leukocytes, continuing until the conditions are poor for C. difficile proliferation because of competition with other bowel flora or the introduction of specific antibiotic therapy. Because the toxins A and B are responsible for the inflammation, agents that bind or eliminate toxins, such as cholestyramine or other resins, may have some efficacy. Gastric acid suppression, especially by potent proton pump inhibitors, has been implicated as a risk factor for C. difficile-related diarrhea in adults. The elderly and neonates may have attenuated gut flora and lower colonization resistance, leading to increased susceptibility to colonization.

The mechanism of toxin A-mediated inflammation begins with receptor binding and internalization by colonocytes, followed promptly by localization in mitochondria causing cessation of production of adenosine 5′-triphosphate (ATP) and generation of reactive oxygen species. Cytoskeletal damage related to Rho protein glucosylation, observed for both toxins A and B, includes disruption of intercellular tight junctions in colonic epithelium, increasing permeability and leading to cell injury. The severe inflammatory response is mediated by toxin A-induced cytokine release, stimulation of enteric sensory neurons to release substance P, calcitonin gene–related peptide, and neurotensin, amplifying mast cell and macrophage activity. A similar mechanism is suspected for the cytopathic effects of the structurally similar toxin B. These processes account for the intense secretory response, inflammation, and necrosis of colonic epithelium exposed to C. difficile toxins.

Diarrhea is a common, often expected, side effect of antibiotic treatment in children and usually is a self-limited, dose-related, and mild consequence, resolving after the course of treatment is completed. These uncomplicated sporadic cases are unlikely to be caused by C. difficile proliferation. In a subset of patients, however, a severe chronic enterocolitis may develop, with profuse watery diarrhea beginning 4 to 10 days after initiation or as late as 4 weeks after discontinuation of antibiotic treatment. The diarrhea may be associated with dehydration, electrolyte depletion, vomiting, and abdominal distention. Hypokalemia, hypoalbuminemia, and metabolic acidosis may occur. The onset of fever, crampy abdominal pain, tenesmus or urgency, and neutrophilic leukocytosis, with or without hematochezia, suggests inflammation of the colon. Significant hypoproteinemia, edema, ascites, and pleural effusion complicate the most severe cases of pseudomembranous colitis and are ominous signs. Dilation of the colon may herald toxic megacolon. The risks of perforation, peritonitis, and sepsis render this outcome a medical and surgical emergency.

Another pattern of antibiotic-associated enterocolitis is diarrhea of variable severity without evolution of signs of frank colitis. The diagnosis in this situation may be delayed for months until colitis develops or C. difficile is considered and the toxin assay is performed. Despite lack of clinical signs of overt pseudomembranous colitis, focal colitis may be found on colonoscopy. Chronic C. difficile diarrhea may resemble other malabsorptive syndromes such as celiac disease or Crohn disease and contribute to growth failure in children.

Rarely, patients have presented with massive stool retention and abdominal distention apparently related to colonic dysmotility in the presence of proliferation of C. difficile and production of toxin and responding to treatment directed against C. difficile.

Most cases of antibiotic-associated enterocolitis occur in patients without underlying gastrointestinal disorders who are treated with antibiotics for other conditions (e.g., respiratory illness, often with questionable indication) or receive short-term preoperative antibiotics. Almost all classes of antibiotics have been implicated in the cause of C. difficile enterocolitis, but the most commonly cited ones are ampicillin and amoxicillin, clindamycin, and cephalosporins, all potent in suppressing normal bowel anaerobic flora but with relatively little activity against C. difficile. The prevalence of ampicillin- and cephalosporin-associated enterocolitis in children reflects the prevalence of administration of these drugs by pediatricians.
Clindamycin, administered relatively infrequently to children, is associated with diarrhea and enterocolitis in children less frequently than it is in adults. Other antibiotics implicated include penicillins, sulfonamides, trimethoprim-sulfamethoxazole, and quinolones. The incidence of antibiotic-associated enterocolitis has not been correlated with specific antibiotic combinations or dosage, although an animal model suggests that duration of therapy is most important.

C. difficile-associated enterocolitis should be suspected in any patient with the acute onset of severe diarrhea or colitis with concomitant or prior oral or intravenous antibiotic treatment; diarrhea beginning after the third hospital day; chronic diarrhea of unknown cause, with or without a history of prior antibiotic treatment; or an exacerbation of suspected or previously documented inflammatory bowel disease (Box 354.1).