(21,24). However, even short courses of antimicrobials administered for prophylaxis can cause
CDI (25). Parenteral and oral antibiotics appear to present similar levels of risk (26).
The only class of drugs, other than antimicrobials, recognized to induce CDI are
antineoplastic agents, primarily methotrexate but also paclitaxel (1). As previously mentioned,
CDI has also been reported without known prior antibiotic exposure (21).
Hospitalization
In hospitals and healthcare facilities, the prevalence ofC. difficilespores in the environment is
high. In addition, patient clustering, a greater likelihood of antibiotic use, and a larger
proportion of elderly patients may facilitate transfer of the organism (1). The rates of
colonization in the feces among hospitalized patients are 10% to 25% and 4% to 20% among
residents of long-term facilities as opposed to 2% to 3% among healthy adults in the general
population. Stay in an intensive care unit and prolonged hospital stay have been reported as
risk factors for CDI (25).
Advanced Age
Patients over the age of 65 years have a 10-fold higher risk of CDI compared with younger
patients (1). Other factors that increase the vulnerability of the elderly are underlying severe
disease, nonsurgical gastrointestinal procedures, and poor immune response toC. difficile
toxins (24). In addition, there is a higher likelihood of comorbidities in older patients that may
lead to more frequent hospitalizations and exposure to antibiotics compared with the younger
population.
Immunity
Host immune response plays an essential role in determining whether patients become
colonized withC. difficileor develop clinical disease. As mentioned previously, most patients
remain asymptomatic following acquisition ofC. difficile(15). Hospitalized patients who are
colonized withC. difficile(both toxigenic and nontoxigenic strains) have been shown to have a
decreased risk of developing CDI (20) even though the protective effect mediated by the
colonization of nontoxigenicC. difficileis not completely understood (7).
Patients with a normal immune system who are exposed to toxin A, mount serum IgG
antitoxin A antibody in response toC. difficile(21). In elderly patients and patients with severe
underlying illnesses, the immunologic response may be blunted leading to lower serum
antibody response to toxin A. Studies have shown that serum and fecal antitoxin A IgG levels
are lower in patients who develop severe, prolonged CDI compared with those with mild
disease (27). One study showed that patients who did not develop increased serum antitoxin A
IgG titers in response to their first CDI episode were 48 times more likely to develop recurrent
CDI than patients who mounted an adequate immune response (28). Elevated serum
interleukin (IL)-8 levels also appear to correlate with impaired humoral immune response to
C. difficiletoxin A and increased susceptibility to CDI (29). Another study found fewer
macrophages and IgA-producing cells in patients with CDI, particularly in those with PMC,
compared with controls with non-C. difficilediarrhea (30).
Other Risk Factors
A systematic review of the literature (24) showed that severity of underlying diseases,
nonsurgical gastrointestinal procedures, presence of a nasogastric tube, and antiulcer
medications were all risk factors associated with CDI. Proton-pump inhibitors (PPIs) neutralized
the gastric acid, and even though the gastric acid is unable to affect the spores, it may kill
vegetative cells and thereby decrease the inoculum (23). The role of PPIs as a risk factor remains
controversial. Some studies have refuted the effect of PPIs in the development of CDI (31), while
others (32) have suggested that PPIs are especially important as a risk factor in CA-CDI.
MICROBIOLOGY
C. difficileis a large (2–17mm), anaerobic, gram-positive, spore-forming, toxin-producing
bacillus. It is closely related toC. sordelliibut not to other toxigenic clostridia, such as
C. perfringens,C. botulinum, andC. tetani.C. difficileis difficult to isolate in the laboratory (hence
274 Hjalmarson and Gorbach