Health Care-Associated Clostridium difficile Infection

Carlene A. Muto

INTRODUCTION

Clostridium difficile is a spore-forming, obligate anaerobic, gram-positive rod. It derives its name from observations in the laboratory. The organism was “difficult” to isolate because of its slow growth compared to other species of Clostridium and its aerointolerant nature when in the vegetative form.
C. difficile is a ubiquitous organism found in the environment; however, its major reservoir is within health care facilities.
C. difficile spores are the transmissible form of the organism and contribute to its survival in the environment and in the host. Spores can survive for months and have been recovered from many common hospital surfaces (toilets, bedpans, bedrails, floors, and thermometers). C. difficile spores are problematic in health care because typical hospital cleaning products have no activity against them.
After exposure to C. difficile, the patient may develop either asymptomatic colonization or Clostridium difficile infection (CDI). Approximately 3% to 5% of healthy adults are colonized with C. difficile, and up to 25% of hospitalized patients are found to be colonized at some point during their hospital stay.
CDI is an inflammatory condition of the colon with clinical illness ranging from mild diarrhea to life-threatening conditions such as toxic megacolon, perforation, or sepsis.
The colonic inflammatory response is a result of toxin-induced cytokines (toxins A and B). Only strains of toxin-producing C. difficile are able to cause disease, and the pathopneumonic condition associated with CDI is pseudomembranous colitis.
Toxigenic strains of C. difficile contain a pathogenicity locus (PaLoc) that harbors the genes tcdA, tcdB, tcdC, tcdR, and tcdE responsible for encoding and regulating toxins A and B. Nontoxigenic strains do not contain PaLoc.
CDI is the most common cause of health care-associated infectious diarrhea.
Recent data suggest that the incidence of health care-associated C. difficile colonization and infection is 29.5 and 28.1 cases per 10,000 patient days, respectively.
Recently, CDI has been associated with increased mortality. This has been attributed to an emerging strain of C. difficile, which has a mutation of the toxin regulatory gene tcdC. This strain (referred to as BI/NAP1/027) produces severalfold more toxin A and B as well as a binary toxin, which may contribute to more severe disease.
Recent data report that among patients colonized or infected with C. difficile, 36% and 63% have the NAP1 strain, respectively.
Acquisition of C. difficile generally occurs after exposure to broad-spectrum antibiotics. Clindamycin, cephalosporins, and beta-lactams have been repeatedly associated with C. difficile. Fluoroquinolones have emerged as a significant risk as well,
particularly with the NAP1 strain. Even short-term exposure to antibiotics, such as that with prophylactic perioperative courses, increases risk for C. difficile.
Traditional risks beyond antibiotic use include advanced age, increased severity of illness, prior hospitalization, use of feeding tubes, gastrointestinal surgery, and the use of proton pump inhibitors; however, risk factors may differ between those merely colonized with the organism and those who develop CDI. These risks appear to be associated with defined host as well as pathogen variables.
- Risks for C. difficile colonization include recent (within 60 days) hospitalization, use of chemotherapy, proton pump inhibitors, H2 blockers, and the presence of antibodies against toxin B.
- Risks for CDI include older age, antibiotics, and use of proton pump inhibitors.

CLINICAL PRESENTATION

A number of clinical features have been described for CDI including malaise, anorexia, abdominal cramping, diarrhea (frequently watery and up to 20 times per day), and fever. Severe disease may cause paralytic ileus or toxic megacolon resulting in no diarrhea.
Physical exam may reveal tenderness (especially in the lower quadrants) and distension. Absence of bowel sounds may indicate severe disease complicated by toxic megacolon. Fever and altered mental status also suggest moderate or severe disease.
Systemic findings, such as fever and leukocytosis, are usually absent in mild disease but are common in moderate or severe disease. Renal failure and shock have also been described.
Laboratory findings consistent with CDI include leukocytosis with bandemia, fecal leukocytes, renal insufficiency, hypoalbuminemia, and elevated lactate.
Visual exam by endoscopy may reveal extensive pseudomembranes or raised yellow-white plaques overlying an erythematous and edematous mucosa. Microscopic evaluation demonstrates an inflammatory exudate composed of mucinous fibrinous material with polymorphonuclear cells.
CT scan may reveal colonic wall thickening and/or pericolonic stranding.
Many facilities employ a scoring criteria to determine severity of disease. Older age (>60), WBC >15,000 or bandemia >10%, elevated serum creatinine (≥1.5 times baseline), low albumin, and altered mental status may be markers for severe or complicated disease.

MANAGEMENT

Historically, metronidazole and oral vancomycin were viewed as equivalent with regard to efficacy and relapse rates, and thus, given the higher cost of oral vancomycin and the concern for development of vancomycin-resistant enterococci, metronidazole (orally or intravenously) was the preferred initial agent of choice.

Table 36-1 Various Stool Testing Methods for Diagnosis of Clostridium difficile Infection^a

Method	Identifies	Advantages	Disadvantages
Cell culture cytotoxin assay	Observes toxininduced cytopathic effect of a cell line inoculated with stool infiltrate	Good sensitivity (67%-86%) but less than newer methods of detection	Requires tissue culture facility, labor intense, takes 24-48 hours, no longer the gold standard
Toxin enzyme immunoassay (EIA)	Toxin A or A and B. Best to use a test that detects both toxins	Fast (2-6 hours), easy to perform, high specificity (84%-100%), most common method used in US hospitals	EIAs generally have variable sensitivity (often <90%). Practice guidelines consider EIA suboptimal for diagnosis of CDI
Glutamate dehydrogenase (GDH) EIA	Common enzyme (GDH) expressed at high levels by all (toxigenic and nontoxigenic) strains of C. difficile	Fast (<1 hour), easy to perform, high negative predictive value (98.5%-99.7%)	Must be combined with another method that detects toxin to verify diagnosis if GDH test is positive
Anaerobic culture	Toxigenic and nontoxigenic C. difficile	High sensitivity, permits strain typing and antibiotic resistance testing during epidemics, useful for comparing new diagnostics	Labor intense (not practical), cannot distinguish between toxin-producing strains, typically takes 2-5 days
Nucleic acid amplification assays	Some assays target conserved regions of tcdB. Some assays detect the PaLoc at a conserved region of tcdA.	Rapid (<1 hour); high sensitivity (77%-100%) and specificity (93%-100%). Gaining popularity for use in hospital clinical microbiology laboratories	Assays vary in methodology, ease of use, instrumentation, and cost
^aSpecimen should be watery, loose, or unformed and promptly submitted to the hospital laboratory.