Individuals in the hospital setting are admitted because of disease, and therefore have unique predisposing factors for enteric infection. Their immune systems may be impaired because of age, seen in infants and the elderly, underlying disease, such as HIV/AIDS, hematological malignancies or organ transplantation, or because of iatrogenic interventions, including the administration of enteral feedings, antibiotics, steroids, or chemotherapy. In a study of patients with renal transplantation, drugs and infectious agents contributed to the development of diarrhea, of which 14.6% were healthcare associated (10). Other underlying medical conditions that can increase susceptibility to acquire infectious diarrhea include renal disease, liver disorders, and diabetes.

Defective intestinal defenses also represent a form of local immune impairment. Gastric acid plays a role in the defense against ingested microorganisms. A lower microorganism inoculum can produce enteric infection with reduced gastric acidity. Achlorydia or hypochloridia may be iatrogenically produced by the use of antacids such as H2 blockers or proton pump inhibitors. Antacids have been shown to greatly facilitate the colonization of the intestine with enteric vaccine strains as well as to increase the frequency of gastrointestinal acquisition of healthcare-associated strains of aerobic gram-negative rods. Anticholinergic medications may have similar effects.

Endoscopic evaluation of patients has become routine with more than eight million or more such interventions being performed annually in the United States. Although infectious gastroenteritis after endoscopic procedures is uncommon, they have been reported. The infectious agents having been acquired by this route include Salmonella sp., C. difficile, and Campylobacter spp. It is difficult to sterilize the instruments employed, since they have complex structures and fragile parts that do not tolerate aggressive sterilization procedures. Preventing transmission of pathogenic microorganisms is of utmost importance, and can be achieved through adequate training of the personnel in charge of this task, stressing meticulous cleaning, the use and adequate contact time with the appropriate disinfectant, and drying thoroughly all parts before storage. Specific guidelines for handling endoscopes have been published (11,12). (see also Chapter 62)

Antibiotic use is perhaps one of the greatest factors in the development of healthcare-associated diarrhea. With the availability of broad spectrum antibiotics with suppressive effects on gut flora, antibiotic-associated diarrhea (AAD) has become an important medical problem in the hospital. Antibiotics such as macrolides and clavulanic acid can alter the motility of the gastrointestinal tract influencing the development of bacterial overgrowth. Microflora of the gut is also altered by antimicrobials, with reductions of anaerobe populations, which can cause an osmotic diarrhea by decreased breakdown of carbohydrates. Alterations of gut flora also predispose to infection by strains of C. difficile, which can be found in the hospital environment. While the first CDD cases followed use of clindamycin, essentially all antibiotics have been associated with development of CDD. It occurs in approximately 2% to 5% of hospital inpatients treated with a variety of antibiotics. The cephalosporins and fluoroquinolones may have the highest rate of CDD development. The rates of diarrhea associated with parenterally administered antibiotics, especially those with enterohepatic circulation, are similar to rates associated with other orally administered agents. Furthermore, AAD may occasionally be caused by other enteric pathogens, including Salmonella, C. perfringens type A, S. aureus, Klebsiella oxytoca, and possibly Candida albicans.

Admission to the hospital also causes individuals to become colonized with hospital microorganisms. Evidence suggests that hospitalized adults have rates of colonization with C. difficile up to 20% to 30% when compared with the outpatient population. Although S. aureus can also be a part of the gut microflora, it has been reported that 7% of patients with AAD have enteric infection with enterotoxinproducing strains. Interestingly, affected patients often can be shown to be carriers of C. difficile (13).

As mentioned before, the hospital setting represents a unique environment. Several studies have demonstrated that increasing lengths of stay in the hospital are a risk factor for acquiring infections unique to this environment. There have also been studies that demonstrate high rates of environmental contamination by C. difficile in hospitals, as well as high rates of colonic colonization associated with hospitalization. C. difficile colonization rates of adult outpatients is seen in 2% to −3%, which increases to 20% to 30% with hospitalization and even higher with longer stays. Hospital food may rarely be a source of healthcare-associated diarrhea, especially outbreaks due to inadequate handling of food. However, the sanitary standards in most hospitals in industrialized countries are high and such outbreaks are unusual. Hospital outbreaks caused by Bacillus cereus (14), Salmonella spp. (15), and C. perfringens (16) have been reported. Crowding and staffing factors play a key role in the transmission of infectious gastroenteritis between patients. A ratio of staff to patients that is insufficient encourages deficiencies in effective hand washing and isolation techniques, especially in critical care areas. Even with careful hand washing, there is still some risk of transmission by direct and successive patient contact. Although most of the time crowding is associated with
low staff to patient ratios, it may also be an independent factor. There is an increase in the incidence of CDD in patients who have physical proximity to other C. difficile-infected patients (17).

CDD follows enteric infection by C. difficile, a spore forming, gram-positive, strictly anaerobic bacteria that produces one or two toxins, toxin A, an enterotoxin and toxin B, a cytotoxin. Both toxins are toxic to human enterocytes. The clinical presentation is broad, and the severity ranges from mild diarrhea to pseudomembranous colitis, sepsis, and death. Between 10% and 20% of all cases of AAD are secondary to C. difficile infection. The likelihood of C. difficile causing disease is higher in persons with more severe disease, particularly when illness is associated with pseudomembranous colitis. Risk factors for CDD include antibiotic exposure resulting in depletion of colonic bacterial flora, hospitalization with its exposure to spores of the microorganism, and host debility (advanced age or other infirmity). The antibiotics showing the highest risk for CDD include the cephalosporins, penicillins, and fluoroquinolones. Traditionally, clindamycin has been an important offender. CDD can also occur in patients who have been exposed to short prophylactic courses of antibiotics (19). Elderly patients >65 years of age have as much as a 20-fold higher risk than younger patients. Other risk factors include underlying disease severity, nonsurgical gastrointestinal procedures, and possibly the use of proton pump inhibitor drugs that cause hypochlorhydria. Patients with a suppressed immune system or poor response to C. difficile toxin are also at increased risk of CDD and disease recurrence.

When a hospitalized patient develops important diarrhea, especially when the illness occurs in an elderly and infirm patient or when fever, dysentery, or leukocytosis are found, a stool should be collected and tested for C. difficile toxins. The most sensitive tests include the cell cytotoxicity test for toxin B, culture of the microorganism followed by testing of isolates for toxigenicity or commercial PCR test. These tests cannot be performed quickly, and they are technically demanding (20). Enzyme immunoassays (EIAs) for detection of toxins A and B are less sensitive (around 70% positivity in known infection), since up to 100 to 1,000 pg of toxin is needed for detection, and can have a false-negative rate up to 40% of cases when compared to cell cytotoxicity assay or culture (21). While culture has very high sensitivity (22), its specificity is low, since the rate of carriage of toxigenic and nontoxigenic strains of C. difficile is high in hospitalized patients. Sensitivity of the EIAs can be increased by repeating the test with other collected stool samples. Glutamate dehydrogenase (GDH) testing does not assay for the toxins but is very sensitive for CDD and can be used to identify true C. difficile-negative cases of diarrhea, while the positive tests need to be confirmed with a toxin-based assay such as an EIA or cytotoxicity assay (23). Other diagnostic modalities include radiographic imaging (CT) and endoscopy, but they are expensive and nonspecific. Finding pseudomembranous colitis at endoscopy is diagnostic, although there are other less common causes of this condition (24).