Clostridium difficile Infection

Clostridium difficile, a causative pathogen in antibiotic-associated colitis,¹ is a slow-growing, spore-forming, gram-positive anaerobic bacillus,² named difficile because it was so difficult to culture. Although this pathogenic spore was first identified in the 1930s,³ its vegetative, toxin-producing form was not recognized as a causative organism in diarrhea and colitis until the late 1970s.^4,5 Since that time, C difficile has become a growing challenge to health care providers for accurate diagnosis, treatment, and containment of the spread of disease. C difficile infection (CDI) often takes a virulent course with associated morbidity, mortality, and health care costs.⁶

EPIDEMIOLOGY

In healthy adult patient populations, 2% to 3% are colonized with C difficile.² The colonization rate among healthy infants is significantly higher, between 60% and 70%, but clinical infection is uncommon.⁷ As the colon becomes populated with flora, between ages 18 and 24 months, the carrier state disappears.⁸

In the hospital setting, 20% to 30% of patients become colonized with the organism by the fecal-oral route, which is facilitated when antibiotic therapy disrupts normal flora in the gut, enabling C difficile spores to proliferate; most patients are asymptomatic.⁵ In 2005, in US acute care hospitals, the incidence of CDI was reported at 84 cases per 100,000 patients.⁹C difficile remains the leading pathogen associated with inpatient antibiotic-associated diarrhea (AAD). It can be identified as the causative organism in 15% to 25% of cases of AAD in hospitalized patients.²

The mortality rate among hospitalized patients rises significantly in those identified with C difficile: 20.6%, compared with 7.0% of matched inpatient controls.¹⁰ ICU admission poses a significant burden of disease: The overall incidence of infection in the ICU population is about 4%. ICU patients who contract CDI have up to a 20% rate of fulminant colitis, a severe form of the disease often necessitating surgery. In this segment of the inpatient population, the mortality rate can approach 60%.⁸

Data analyzed by Zilberberg¹¹ have demonstrated a significant increase in C difficile–­associated infections in US hospitals in recent years. In 2001, the number of discharged patients with documented CDI was approximately 134,000, compared with 291,000 in 2005. The rising incidence of CDI has been attributed to increased antibiotic use, aging of the population, an increasing rate of comorbid conditions, fluoroquinolone resistance, and increased suspicion for the illness, which has led to increased use of testing.^12,13

Of Significant Concern

Recurrent disease poses a particular challenge to the health care system. It has been reported that recurrence rates for CDI are between 15% and 35% after a first bout and between 33% and 65% after subsequent episodes of infection.^2,14

A hypervirulent strain, the North American pulsed-field gel electrophoresis type 1 (NAP1/B1/027) has been implicated in several C difficile outbreaks.¹⁵ This subtype, which is especially resistant to fluoroquinolones,¹ produces toxins earlier and in much greater quantities, including toxins A and B at levels 15 to 20 times greater than those seen in less virulent subtypes.^4,12 Thus, the NAP1 strain is implicated in more severe disease and is more lethal.¹⁶ Affected patients have a 30-day mortality rate twice as high as that among patients with other strains of C difficile.¹²

The calculated cost of CDI adds between $2,454 and $7,179 in nonreimbursable costs per hospitalized patient, and an additional 3.6 to 7.0 days to their hospital stays.¹⁷ Estimates for CDI treatment in the US range from $436 million to $3 billion per year.^6,17

Community-Acquired CDI

Community-acquired C difficile infection (CA-CDI) is a subtype that develops in patients who have not been hospitalized in the previous year,¹⁸ with incidence recently reported at 11.16 cases per 100,000 person-years.¹⁹ Affected patients tend to be younger than those with hospital-acquired infection and to have a less severe disease course. To meet the criteria of this subgroup, according to recent clinical practice guidelines jointly issued by the Society for Healthcare Epidemiology of America and the Infectious Diseases Society of America (SHEA-IDSA),¹ a patient may have developed symptoms no sooner than 12 weeks after hospital discharge (if any hospitalization occurred).

It is always important to perform a thorough history in patients with suspected CA-CDI to assess for recent hospitalizations and antibiotic use. In a retrospective study published in 2011, Kuntz et al¹⁹ found that CA-CDI–affected patients were six times as likely as healthy controls to have taken antimicrobials within 180 days before illness (including beta-lactam/beta-lactamase inhibitors, cephalosporins, clindamycin, fluoroquinolones, and penicillin) and twice as likely to have used gastric acid suppressants in that time.

One emerging theory is that CA-CDI is spread through food-borne illness. Unlike the vegetative form that resides in the bowel, C difficile spores are resistant to temperatures at which food is cooked (as they are to alcohol and many other disinfectant agents).⁵ Several studies have shown that livestock can harbor C difficile.¹²