Clostridium difficile Infection (CDI)

What is Clostridium difficile? 

First isolated in 1935 and named for its difficult isolation from the feces of infants, Bacillus difficile is an anaerobic, gram-positive, spore-forming, toxin-producing bacteria spread by the fecal-oral route. By the 1970s, this bacillus was renamed Clostridium difficile and its toxins were implicated as a major cause of diarrhea and as the cause of pseudomembranous colitis (PMC). C. difficile infection (CDI) has historically been precipitated by the use of broad-spectrum antibiotics that disrupt the normal intestinal microbiome that allows for the overgrowth of C. difficile . There is an increasing prevalence of sporadic and community-acquired cases occurring in healthy hosts without prior antibiotic exposure. Although some healthy adults are asymptomatic carriers, patients with CDI can experience a spectrum of symptoms, ranging from a self-limited course of diarrhea to PMC. Severe cases of CDI can cause ileus and toxic megacolon, necessitating surgery, intensive care unit (ICU) admission, and can result in death.

How is CDI defined? 

Although 20% to 30% of persons who take antibiotics develop diarrhea, only 10% to 20% of these cases are caused by C. difficile . CDI has been defined as three or more unformed or watery stools for 1 to 2 days with associated C. difficile toxin detection in stool or by culturing the toxigenic C difficile .

What causes PMC? 

PMC is due to overgrowth of C. difficile, which causes disease by production of two toxins, A and B. C. difficile strains that do not produce toxins are not pathogenic. Toxins A and B cause mucosal damage and inflammation of the colon by disrupting the actin cytoskeleton of the intestinal epithelial cells while triggering an inflammatory cascade. The inflammatory exudate seen in the colon is called a pseudomembrane, like that seen in diphtheria infection. Although it is a sign of severe CDI, pseudomembranes can also sometimes be seen with ischemic colitis.

What are the risk factors for CDI? 

The common risk factors for CDI include antibiotic exposure (usually within the prior 2 months), recent hospitalization (especially surgical patients, ICU patients, and posttransplant patients), age older than 65, comorbidities, and immunosuppression. Other risk factors include invasive procedures (with higher risk for gastrointestinal [GI] procedures), renal failure, chemotherapy, and residence in long-term care facilities. There are also reports of severe CDI in previously low-risk populations such as pregnant women. Newer risk factors include the presence of inflammatory bowel disease and taking a daily proton pump inhibitor (PPI). Hospital settings remain an important reservoir, in part, because the spores of the anaerobic bacillus, C. difficile, can survive for up to 5 months. As many as 20% to 30% of hospitalized patients are colonized with C. difficile and two thirds of these infected hospitalized patients have historically been asymptomatic carriers.

Which antibiotics are most commonly implicated? 

Clindamycin and cephalosporins (especially third generation) have been most commonly associated with CDI in the past, followed by expanded-spectrum penicillins. More recently, fluoroquinolones have been implicated as a significant risk factor. Of note, CDI can occur with any antibiotic, even single-dose preoperative antibiotics.

Why do some people develop C. difficile diarrhea and others are simply colonized? 

Up to 15% of healthy adults are carriers of C. difficile without symptoms; in newborns and healthy infants, the carriage rate is as high as 84%. Studies of patients with C. difficile colonization have shown that serum levels of immunoglobulin (Ig) G antibody against toxin A have been associated with protection from disease expression and prevention of recurrences.

How have the epidemiologic characteristics of CDI changed?

Since the early 2000s, the morbidity and mortality of CDI has been increasing with epidemics reported in the United States, Canada, Europe, and Japan. The U.S. Centers for Disease Control and Prevention has reported an increase in hospital billing attributed to CDI; there were 82,000 reported cases of CDI in 1996, 178,000 reported cases in 2003, and 250,000 reported case in 2005. A 2008 study showed a CDI prevalence rate of 13.1 per 1000 inpatients. There is also evidence to suggest the severity of CDI is increasing with more frequent hospitalizations, colectomies, and mortality. C. difficile -related mortality by listing on death certificates in the United States rose from 5.7 deaths per million in 1999 to 23.7 deaths per million in 2004. On review of U.S. data through 2007, CDI was the most common cause of gastroenteritis-associated death (18.7 per million). In addition to this CDI epidemic, cases are now being reported among lower-risk patients in the community.

What accounts for the changing epidemiologic characteristics of CDI? 

The changing epidemiologic findings of CDI has been attributed, in part, to the evolution of a hypervirulent strain, designated BI/NAP1/027 (restriction-endonuclease analysis group BI, North American Pulsed Field type 1, polymerase chain reaction ribotype 027). This strain has a gene deletion, which accounts for increased toxin production. With the emergence of this strain, cases have been more severe. Coupled with this increased toxin production, the strain has resistance to fluoroquinolones and clindamycin. Other hypervirulent strains have been identified.

What possible factors mediate the severity of CDI?

The fluoroquinolone-resistant B1/NAP1/027 strains have been associated with higher concentrations of both toxin A and B in vitro. The B1/NAP1/027 strain also carries two genes of interest. The first gene, tcdC, has an 18-base pair deletion; this mutation renders the tcdC gene ineffective in inhibiting the production of toxins A and B, which may explain its pathogenicity. The second gene encodes a C. difficile binary toxin (CDT) similar to the iota toxin found in Clostridium perfringens, but it is not known if it contributes to pathogenicity. Additionally, immunocompromised patients often have more severe disease. Another consideration is the effect of CDI in the disruption of gut microbiota. The intestinal microbiome makes up a complex, interdependent ecosystem responsible for food digestion, immune system activation, vitamin production, and protection from invasive nonindigenous bacteria, which is known as colonization resistance. Alteration of this microbiome likely contributes to patients’ symptoms.

How is the diagnosis of CDI made?

The diagnosis of CDI has become increasingly more rapid as newer testing modalities have become available. Nucleic acid amplification tests, such as polymerase chain reaction (PCR) for C. difficile toxin genes are now superior to previously used enzyme immunoassay (EIA) tests. While EIA tests are overall specific, they should not be stand-alone tests. Glutamate dehydrogenase (GDH) testing checks for GDH, a Clostridium antigen, but it is not specific to C. difficile; therefore this test can be used as a screen, but a positive test requires further confirmation of C. difficile toxin presence, usually with PCR. Because C. difficile carriage is increased in patients on antibiotics, only stools from patients with diarrhea should be tested for C. difficile . Repeat testing should be discouraged as a negative test is positive less than 5% of the time on testing of a second stool. Additionally, because diagnostic tests may stay positive for up to a month, a test of cure is generally not advised. Of note, regardless of testing modality, if the patient presents with severe illness and concern for CDI is high, empiric antibiotic therapy should be initiated.

Available Tests for the Diagnosis of CDI

PCRHighHighVery specific and sensitive.
Quick, but more expensive.
Repeat PCR within 7 days is low yield.
GDHHighLowGood screening test.
If negative, no further testing required.
If positive, requires confirmatory test for toxin, often with PCR.
Tissue cytotoxin B assayHighHighGold standard for laboratory reference testing (detects up to 10 pg toxin), but expensive and rarely used clinically.
Requires technical expertise.
Results not ready for 24-48 hours.
Toxin A enzyme immunoassayModerateModeratePrior to PCR, this was the most widely used test.
Quick and inexpensive.
Will miss toxin A−/B + strains.
Toxin A and B enzyme immunoassayModerateHighDetects toxin A−/B + strains.
Toxin B is more potent than toxin A and can cause disease in the absence of toxin A.
Stool cultureModerateModerateCarriers test positive.
Results unavailable for 72 hours.
Does not distinguish nonpathogenic vs. pathogenic strains, so not useful diagnostically.
Toxigenic stool culture useful in evaluation of epidemics and as a laboratory reference test.
EndoscopyLowModerateLow sensitivity, but the presence of pseudomembranes strongly suggest C. difficile , can also be seen with ischemia.

GDH, Glutamate dehydrogenase; PCR, polymerase chain reaction.

What are the typical findings on colonoscopy? 

Colonoscopy may be normal or show nonspecific colitis. With severe disease, the colon mucosa has creamy white-yellow plaques (pseudomembranes). Histologic studies show that the pseudomembrane usually arises from a point of superficial ulceration, accompanied by acute and chronic inflammation of the lamina propria. The pseudomembrane is composed of fibrin, mucin, debris of sloughed mucosal epithelial cells, and polymorphonuclear cells.

What are the hallmarks of severe CDI? 

Severe CDI is defined as hypoalbuminemia (< 3 g/dL), abdominal distention or tenderness and/or leukocytosis (> 15,000). There are several scoring systems aimed at assessing the clinical severity of CDI cases, although none have been very useful in daily practice beyond recognizing the previously discussed factors, which often correlate with severity.

What are the hallmarks of severe and complicated CDI? 

Patients with severe and complicated CDI are critically ill. Clinical features can include fever, severe leukocytosis or leukopenia (often with white blood cells > 35,000 or < 2000), hypoalbuminemia, and abdominal distention. Patients may be in shock with hypotension and an elevated serum lactate of more than 2.2 mmol/L. Inflammatory markers, such as C-reactive protein may be elevated. Ileus may also be present. Severe colitis can result in toxic megacolon and progress to colonic perforation and death with multiorgan failure. These patients should be treated with high-dose oral vancomycin and intravenous (IV) metronidazole. Urgent surgical consultation is indicated.

When is treatment indicated? What antibiotics are used? 

Implicated antibiotics should be discontinued, if possible. Clinical suspicion should prompt empiric treatment in patients with severe illness while awaiting test results. Three drugs are used for therapy: metronidazole, vancomycin, and fidaxomicin. Metronidazole has been first line in the past because of its low cost and the concern that oral vancomycin use might promote emergence of vancomycin-resistant enterococci in hospitalized patients. Historically, the efficacy of metronidazole has been equal to that of vancomycin; however, reports of metronidazole treatment failures rates have been increasing to as high as 22% to 38% during the past several years. In severe cases of CDI, the use of oral vancomycin is recommended because of its faster efficacy and higher cure rates (97% vs. 76%). Typical treatment courses are 10 to 14 days. The Food and Drug Administration (FDA) has also approved fidaxomicin, a poorly absorbed antibiotic, for treatment of mild to moderate CDI. Although similar in efficacy to vancomycin, it is more expensive. More severe cases often require additional treatment with IV metronidazole, as well as vancomycin enemas. Patients with severe and complicated disease who do not respond to maximal medical therapy may require surgical consultation with surgical options that include total colectomy or loop ileostomy with colon lavage of vancomycin postoperatively. For a summary of CDI treatments.

Treatment Options for Clostridium difficile Infection

CDIDrug and DoseComment
Mild-moderateMetronidazole 500 mg PO tid × 10 daysInexpensive; avoid in pregnancy and with breast feeding. Switch to vancomycin if no response to metronidazole in 72 hours.
SevereVancomycin 125 mg PO qid × 10 daysCan increase to 250 mg qid if poor response.
ComplicatedMetronidazole 500 mg IV tid and Vancomycin 500 mg PO qid +/– Vancomycin enemas, 500 mg qidPatients with ileus, recent abdominal surgery, unable to take PO. Patients who can tolerate PO should receive +/– vancomycin enemas, 500 mg qid enteral feeding, if possible.
RecurrentRepeat metronidazole or vancomycin pulse regimenConsider FMT after 3 recurrences

FMT, Fecal microbiota transplantation; IV, intravenous; PO, by mouth; qid, four times daily; tid, three times daily.

When should you expect a response to treatment? 

Response to treatment usually occurs within 3 to 5 days. Do not use antidiarrheals because the number of stools must be monitored to determine response to treatment. There is no evidence to support laboratory testing for cure; therefore this should not be done. Both toxin A and B EIA may remain positive for as long as 30 days, including in patients with resolution of symptoms; false positives may further complicate patient care.

What other treatment options are under development and investigation? 

Other antibiotics and treatments have been tried, but not proven to be successful by randomized controlled trials and are not FDA approved for treatment of CDI. These include tigecycline, nitazoxanide, and IV Ig. Some case reports show benefit of rifaximin as an adjuvant to vancomycin, but this is not an FDA-approved treatment. Fecal microbiota transplant, or the infusion of stool from a healthy donor to a recipient with CDI, is not an established treatment in initial cases of CDI, but has shown benefit in recurrent CDI.

What is recurrent CDI and how is it treated? 

Despite therapy, approximately 10% to 20% of patients have CDI recurrence , possibly because of persistent spores despite initial elimination of the C. difficile bacteria. Initially, the same treatments should be tried with metronidazole or vancomycin at standard doses. Some patients benefit from a pulsed regimen of vancomycin, such as 125 mg by mouth four times a day for 10 days, then 125 mg every day every 3 days for 10 doses. Additionally, research on monoclonal antibodies directed against toxins A and B has shown promising results.

What is the role of fecal microbiota transplantation (FMT) for recurrent CDI? 

Although the goal of CDI has been focused on eradication of the pathogen with antibiotic treatment, the goal of FMT is to reestablish the diverse normal microbiome within the large intestine. Studies have shown CDI patients have decreased microbiome diversity with less Bacteroidetes and Firmicutes bacteria compared to normal hosts. Instead, recurrent CDI patients have high levels of Proteobacteria and Verrucomicrobia. These findings support the hypothesis that CDI results from altered intestinal microbiota, which FMT aims to restore. FMT repopulates bacteria relatively quickly, and the effect persists. FMT is viewed as a success if the patient does not have a CDI recurrence within 8 weeks. Multiple studies and systematic reviews have described high levels of success with FMT, with response rates of up to 98%.

How can we control C. difficile epidemics in hospitals? 

CDI is a leading cause of hospital-associated GI illness with significant cost to the health care system estimated at $3.2 billion annually. Prevention of CDI involves the judicious use of antibiotics as well as vigilant environmental control. Once diagnosed, patients with CDI should be isolated in rooms with personal bathrooms until their diarrhea resolves. Contact enteric precautions should be initiated; C. difficile spores have been cultured from patient bathrooms, bedpans, stethoscopes, and blood pressure cuffs. Once patients depart from their isolation rooms, these rooms should be cleansed with a 10% bleach solution. Clostridia spores are not vulnerable to alcohol; therefore handwashing with soap and water and use of disposable equipment helps to prevent the transmission of C. difficile in health care settings. Additionally, there is ongoing research to determine potential C. difficile vaccines.


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