• Clostridium difficile infection is diagnosed by a combination of clinical and laboratory findings.
• Diagnosis requires a positive test for the presence of C. difficile toxins.
• C. difficile cytotoxin assay is the most sensitive and specific test but requires 72 to 96 hours to complete.
• Enzyme immunoassay testing for toxin A and or B has a variable sensitivity and specificity and a turnaround time of about 24 hours and correlates well with disease activity.
• Polymerase chain reaction testing has a high sensitivity and specificity and a turnaround time of less than 4 hours; correlates less with disease activity, thus identifying patients with colonization as well as active infection.
• Laboratory testing for C. difficile toxins should only be performed on unformed stool, and is not useful as a test of cure.
• Pathologic findings can help to confirm diagnosis.
• If possible, the clinician should first consider discontinuing concurrent antibacterial therapy.
• Antimotility agents should be avoided because they can decrease gut motility and increase the risk of toxic megacolon.
• Treatment should be initiated only after a positive test result for C. difficile toxin unless the patient is at high risk for C. difficile infection or is severely ill, in which case empirical therapy is justified.
• Antimicrobials, active against C. difficile, may be administered orally, intravenously, or rectally. Oral therapies are preferred.
• Treatment recommendations depend on the severity of the disease and whether the patient has a first-time diagnosis or recurrence.
• Clinical parameters that guide treatment include increasing age, leukocytosis, elevation of serum creatinine, and presence of hypotension, shock, ileus, or megacolon.
• Antimicrobials used are oral or intravenous metronidazole (Flagyl),1 oral and rectal1,6 vancomycin (Vancocin), and fidaxomicin (Dificid).
1 Not FDA approved for this indication.
6 May be compounded by pharmacists.
Pseudomembranous colitis is an inflammatory disease of the colon that is almost always associated with the toxin-producing bacteria Clostridium difficile. In very rare cases, other organisms can be responsible. In this article I discuss C. difficile as an important cause of pseudomembranous colitis.
Epidemiology and Risk Factors
C. difficile is the most common infectious cause of health care– associated diarrhea. Both the incidence and the attributable mortality of C. difficile infection is increasing. Studies in U.S. hospitals showed that mortality due to C. difficile infection nearly quadrupled from 1999 through 2004. An active population and laboratory based study done by the U.S Centers for Disease Control and Prevention in 2011 suggested that 453,000 new cases occur in the U.S. annually; with a 30 day mortality of 6.4%. Higher rates of infection were found in whites, females, and those > 65 years of age. A Canadian study in 2011 prospectively followed 5422 hospitalized patients and showed that 7.4% had asymptomatic colonization only (60% of these were positive at the time of admission); 2.8% developed C. difficile infection during hospitalization. Colonization rates of hospitalized patients range from 0–22% with a mean of 8%.
Additional risk factors for the development of C. difficile infection include antimicrobial or chemotherapeutic drug exposure, severe underlying illness, prior hospitalization (acute or long-term care), use of feeding tubes, recent gastrointestinal surgery, and use of proton pump inhibitors. Exposure to antibiotics has been shown to lead to an alteration in the type and quantity of bacterial species found in the normal human intestinal microbiome. Most antibiotics have been associated with C. difficile infection. Increased antimicrobial duration and dosage appear to be associated with higher risk of C. difficile infection.
Epidemic strains have been described by pulsed-field gel electrophoresis, (NAP1,4,7,11 etc.), that are associated with decreased regulatory gene function and increased toxin production. The risk and severity of infection are increased following exposure to the NAP1 strains. Failure of standard first-line therapy for C. difficile infection may increase to 10% to 35% during infection with NAP strains.
C. difficile infection occurs rarely without prior antibiotic exposure. Healthy peripartum women, children, and postsurgical patients rarely develop C. difficile infection after a single dose of antibiotics. Newborns have a higher rate of colonization, but generally a low rate of C. difficile infection.
Infection is costly. It is estimated that each episode costs the U.S. health care system $3,427– $16,307 per episode or $1.2 billion–$5.9 billion per year.
Microbiology and Pathophysiology
C. difficile is a Gram-positive, spore-forming, anaerobic rod. The name “difficile” was given because it was historically difficult to grow in culture. C. difficile can exist as either a spore or vegetative form. The vegetative form is highly oxygen sensitive; slight exposure can kill the bacteria. The spore form is highly heat-stable and can survive harsh conditions such as the high acidity of the stomach. Spores have been shown to resist many commercial disinfectants. C. difficile reproduces in intestinal crypts and releases exotoxins A and B, leading to severe inflammation. Toxin A (enterotoxin) attracts neutrophils and monocytes, and toxin B (cytotoxin) degrades colonic epithelial cells. Most strains of C. difficile produce both toxin A and B. Toxins disrupt cell membranes and cause shallow ulcerations on the intestine mucosal surface. Ulcer formation leads to the release of proteins, mucus, and inflammation manifesting as a pseudomembrane. A pseudomembrane is virtually pathognomonic for C. difficile infection.
Transmission occurs via the fecal–oral route, person to person, or via fomites. Following exposure to antibiotics, the normal gut flora is altered, allowing C. difficile to become more dominant. Exposure to C. difficile spores may result in no acquisition, asymptomatic colonization, mild diarrhea, or infection. The incidence of colonization increases at a steady rate during hospitalization, suggesting ongoing exposure to spores. A recent meta-analysis of 19 studies and over 8700 patients suggests that colonization at the time of hospital admission is associated with an increased risk of subsequent C. difficile infection.
The risk of colonization was associated with hospitalization during the prior 3 months.
Evidence suggests that the host immune response to spore exposure is important in determining the clinical outcome. Approximately 60% of people have detectable levels of antibodies to toxin A and B. It is likely that prior exposure to C. difficile spores or related clostridial species and subsequent colonization stimulates antibody production and immunity. Clostridium difficile has been found to be capable of creating a biofilm in vitro, which is capable of producing toxin while decreasing the antibacterial activity of antibiotics such as metronidazole (Flagyl). Various studies are attempting to define the role of active or passive immunotherapy, including vaccination with nontoxigenic C. difficile, to prevent C. difficile infection.
C. difficile infection is diagnosed by a combination of clinical and laboratory findings. Diarrhea is defined as the passage of three or more unformed stools in a 24-hour period. Symptoms include fever, diarrhea, and cramplike abdominal pain. Patients can have nausea, vomiting, or hematochezia. In severe cases, abdominal tenderness and distention are present. Signs of septic shock can develop. The white blood cell count (WBC) is often elevated, as high as 30,000 to 50,000 cells/µL. The extent of leukocytosis frequently correlates with disease severity. Plain abdominal radiographs might show distended loops of bowel or, in severe cases, toxic megacolon. Computed tomography (CT) image findings include colonic wall thickening and dilatation, mesenteric edema, and, rarely, perforation. Endoscopy can reveal pseudomembranes. However, sigmoidoscopy or colonoscopy may be complicated by perforation in severely ill patients and should be performed with caution.
The differential diagnosis includes bacterial causes such as Shigella, Salmonella, or Campylobacter species, protozoan infections such as Entamoeba histolytica or Strongyloides stercoralis (immunosuppressed patients), inflammatory disorders such as ulcerative colitis or Crohn’s disease, drug toxicity (e.g. chemotherapeutic agents), and vascular disorders such as ischemic bowel disease.
Various tests have been developed for the diagnosis of C. difficile infection. Cytotoxin assays for C. difficile toxin are highly sensitive and specific and remain the gold standard but are labor intensive and may take up to 4 days.
Enzyme immunoassays (EIA) for toxin A and or B detect toxin production. Sensitivity is 63%–94% and specificity is 75%–100%. The turnaround time is usually 24 hours. These tests correlate well with clinical disease activity.
More recently, molecular tests such as polymerase chain reaction (PCR) have been developed and can be performed in less than 4 hours. The sensitivity is approximately 93% and specificity is 97%.
These tests target toxin genes and do not always correlate with clinical disease. Since the introduction of PCR the number of cases diagnosed has increased further (though some may represent colonization).
Thus, positive C. difficile testing must be correlated with clinical disease activity to determine if treatment is indicated. Some authors have recommended two-step testing with a positive PCR result to be followed by EIA toxin assay.
If possible, the clinician should first consider discontinuing concurrent antibacterial therapy, unless there is a compelling clinical indication to continue. Antimotility agents should be avoided because decreased gut motility can increase the potential for tissue toxin exposure and toxic megacolon. Treatment for C. difficile infection should be initiated only after a positive test result unless the patient is at high risk for C. difficile infection or is severely ill, in which case empirical therapy is reasonable even with negative test results.
Antibacterials used to treat C. difficile infection can be administered orally, intravenously, or rectally. Oral therapies are preferred. Oral metronidazole (Flagyl), a nitroimidazole antibiotic, is eliminated primarily in the urine, although 6% to 15% is eliminated in the feces. Oral vancomycin (Vancocin) is not absorbed in the gastrointestinal tract and is eliminated in the feces.
The Society for Healthcare Epidemiology of America (SHEA) and the Infectious Diseases Society of America (IDSA) published treatment guidelines in 2010. Recommendations for the treatment of C. difficile infection depend on the severity of the disease. Clinical parameters that correlate with severity include increasing age, leukocytosis, and elevation of the serum creatinine.
For patients with a first episode of C. difficile infection that is mild to moderate, metronidazole (Flagyl)1 500 mg PO three times per day for 10 to 14 days is recommended. Supportive clinical data in mild to moderate disease includes a WBC count less than 15,000 cells/µL and a serum creatinine less than 1.5 times the premorbid level.
For patients with a first episode that is severe, vancomycin (Vancocin) 125 mg PO for 10 to 14 days is recommended. A WBC count of at least 15,000 cells/µL or a serum creatinine at least 1.5 times the premorbid level suggests a severe infection.
Patients with an initial episode that is complicated by hypotension, shock, ileus, or megacolon should be treated with vancomycin 500 mg PO 4 times per day,3 plus metronidazole1 500 mg IV every 8 hours. If the patient has a complete ileus, the clinician may consider adding a rectal instillation of vancomycin1,6 500 mg every 6 hours.
The response to therapy should be monitored clinically. Reversal of hemodynamic instability, decreasing stool frequency, and a declining WBC count are objective measures of response. Stool tests for C. difficile toxin are not valuable for monitoring disease elimination, because these tests can remain positive following improvement.
Complications and Recurrence
Another challenging problem in C. difficile infection is recurrence. Recurrence is defined as another episode that occurs within eight weeks of the initial episode. Recurrence occurs in approximately 20% to 30% of cases following resolution of the initial episode. Continued use of antibacterials (other than treating agents), increased age, longer hospitalization, severe underlying disease, and inadequate antitoxin antibody response are risk factors for relapse. Even though treatment failure and relapse are common, resistance to metronidazole or vancomycin is uncommon.
Treatment is the same for the first recurrence as for a primary episode. For additional recurrent episodes, consider an infectious diseases consultation and or a vancomycin taper with a pulsed dose regimen.3 This consists of vancomycin 125 mg PO 4 times per day for 2 weeks, followed by 125 mg PO 2 times per day for 1 week, followed by vancomycin 125 mg PO once daily for 1 week, followed by 125 mg PO once every 2 to 3 days for 2 to 8 weeks.
Fidaxomicin (Dificid), a macrocyclic antibacterial, has greater in vitro activity against C. difficile than vancomycin does, and it is also nonabsorbed. Fidaxomicin (Dificid), 200 mg PO twice daily was compared to vancomycin 125 mg PO four times daily in patients with C. difficile infection. Fidaxomicin was found to be noninferior to vancomycin in this trial and associated with a statistically smaller rate of recurrence of C. difficile infection. Fidaxomicin may be considered as an alternative to vancomycin for management of recurrences.
Another option for recurrent C. difficile infection is fecal reconstitution or fecal microbiota therapy (FMT). The goal is to restore normal colonic flora. Healthy donor stool from a related or unrelated donor is infused via colonoscopy, intraduodenal, or by frozen capsule. Numerous studies have shown the efficacy of FMT, although the exact place, timing and mode of installation continue to be under evaluation. Donor stool must be screened for infectious agents prior to installation. Additional promising options for prevention of recurrences include the addition of monoclonal antibodies directed against C. difficile and the oral administration of non toxigenic C. difficile strains.
Probiotics7 are live organisms that seek to restore the normal gastrointestinal microflora. Most studies have employed Lactobacillus species or Saccharomyces boulardii in an effort to prevent, or treat C. difficile infection. A few small studies have shown benefit, but none are able to demonstrate adequate statistical power for efficacy.
Occasional cases of fungemia or bacteremia have been reported in immunocompromised patients and those with central venous catheters treated with probiotics. Probiotics should be avoided in these patients.
Total colectomy is often considered as a last measure for patients who remain critically ill despite standard therapy. The exact indications for surgery are not clear, though refractory shock, signs of peritonitis, megacolon, and multiorgan failure are most often cited. As expected, the mortality rate after total colectomy is high, ranging from 35% to 80%. Neal and colleagues reported that in a series of 42 patients, performance of a diverting loop ileostomy and intraoperative colonic lavage with polyethylene glycol, followed by postoperative antegrade vancomycin flushes, resulted in 19% mortality and 93% colon preservation.
Given the current difficulties in controlling the spread of C. difficile, prevention is critical. C. difficile spores resist desiccation and can survive in the hospital environment for months. Environmental contamination is highest in and around the rooms of patients with C. difficile infection. The risk of hospital associated C. difficile has been found to be increased for patients occupying the bed of a previous patient who received antibiotics. Items that have been found to harbor C. difficile spores include clothing, blood pressure cuffs, telephones, toilets, doorknobs, oral and rectal thermometers, and other medical equipment. In addition, the hands of health care workers have been found to be a vehicle of Current recommendations for prevention of transmission of C. difficile include the following. Careful hand hygiene with soap and water is essential. Programs to monitor the compliance and technique of hand hygiene are recommended. Alcohol-based hand rubs, which are widely used, have been shown to be less effective at removing spores than conventional hand washing. Thus alcohol-based hand rubs should not be used for C. difficile isolation. Barrier precautions with gowns and gloves should be used. Programs to ensure adequate and effective cleaning of health care facilities following use are recommended. Disposable electronic thermometers are recommended. Antimicrobial stewardship programs aimed at promoting the judicious use of antibacterial therapy have been found to be effective in reducing C difficile infection rates should be employed. In view of recent data that colonization at the time of admission increases the risk for C. difficile infection, studies have been initiated to determine if contact isolation for C. difficile colonized patients will be beneficial in decreasing transmission.
1. Agrawal M., Aroniadis O.C., Brandt L.J., et al. The long-term efficacy and safety of fecal microbiota transplant for recurrent, severe, and complicated Clostridium difficile infection in 146 elderly individuals. J Clin Gastroenterol. 2016;50(5):403–407.
2. Bignardi G.E. Risk factors for Clostridium difficile infection. J Hosp Infect. 1998;40:1–15.
3. Cohen S.H., Gerding D.N., Johnson S., et al. Clinical practice guidelines for Clostridium difficile infection in adults: 2010 update by the Society for Healthcare epidemiology of America (SHEA) and the Infectious diseases Society of America (IDSA). Infect Control Hosp Epidemiol. 2010;31:431–455.
4. Feazel L., Malhotra A., Perencevich E., et al. Effect of antibiotic stewardship programmes on Clostridium difficile incidence: a systematic review and meta-analysis. J Antimicrob Chemother. 2014;69:1748–1754.
5. Hsu J., Abad C., Dinh M., et al. Prevention of endemic healthcare-associated Clostridium difficile infection: reviewing the evidence. Am J Gastroenterol. 2010;105:2327–2339.
6. Johnson S. Recurrent Clostridium difficile infection: A review of risk factors, treatments, and outcomes. J Infection. 2009;58:403– 410.
7. Kyne L., Warny M., Qamar A., et al. Asymptomatic carriage of Clostridium difficile and serum levels of IGG antibody against toxin A. N Engl J Med. 2000;342:390–397.
8. Kwon J.H., Olsen M.A., Dubberke E.R. The morbidity, mortality, and costs associated with Clostridium difficile infection. Infect Dis Clin N Am. 2015;29:123–134.
9. Lessa E., Mu Y., Bamberg W., et al. Burden of Clostridium difficile infection in the United States. N Engl J Med. 2015;372:825–834.
10. Loo V.G., Bourgalt A., Poirier L., et al. Host and pathogen factors for Clostridium difficile infection and colonization. N Engl J Med. 2011;365:1693–1703.
11. Louie T.J., Miller M.A., Mullane K.M., et al. Fidaxomicin versus vancomycin for Clostridium difficile infection. N Engl J Med. 2011;364:422–431.
12. Neal M., Alverdy J.C., Hall D.E., et al. Diverting loop ileostomy and colonic lavage: An alternative to total abdominal colectomy for treatment of severe, complicated Clostridium difficile associated disease. Ann Surg. 2011;254:423–427.
13. Polange C.R., Gyorke C.E., Kennedy M.E., et al. Overdiagnosis of Clostridium difficile infection in the molecular test era. JAMA Intern Med. 2015;175:1792–1801.
14. Semenyuk E.G., Laning M.L., Foley J., et al. Spore formation and toxin production in Clostridium difficile biofilms. PLoS One. 2014 Jan 30;9(1):e87757.
15. Van Nood E., Vrieze A., Nieuwdorp M., et al. Duodenal Infusion of Donor Feces for Recurrent Clostridium difficile. N Engl J Med. 2014;368:407–415.
1 Not FDA approved for this indication.
3 Exceeds dosage recommended by the manufacturer.
6 May be compounded by pharmacists.
7 Available as a dietary supplement.